Anti-SARS-CoV-2 fusion peptides

ABSTRACT

Anti-SARS-CoV-2 fusion peptides are provided. The anti-SARS-CoV-2 fusion peptides include peptide sequences corresponding to the sequence of the SARS-CoV-2 fusion complex heptad repeat domain HR2 and having at least one artificial mutation. The anti-SARS-CoV-2 fusion peptides may be 39-mers, such as peptides #121 (SEQ ID NO: 2) and #125 (SEQ ID NO: 5). These peptides may competitively bind to SARS-CoV-2 and prevent either membrane mediated SARS-CoV-2 fusion, endocytosis-mediated viral entry, or both. The anti-SARS-CoV-2 fusion peptides may be administered to a subject in need thereof to inhibit or prevent SARS-CoV-2 cellular entry.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 63/093,157, filed on Oct. 16, 2020.

INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED IN COMPUTER READABLEFORM

The Applicants hereby incorporate by reference the sequence listingcontained in the ASCII text filed titled 32087_34Sequence_Listing_ST25.txt, created Apr. 27, 2021, and having 3 KB ofdata.

BACKGROUND 1. Field

The disclosure of the present patent application relates tobiotechnology, and particularly to anti-SARS-CoV-2 fusion peptides andmethods of using said peptides.

2. Description of the Related Art

The SARS-CoV-2 pandemic that began in 2019 has posed a significantthreat worldwide. In the past two decades, three coronaviruses haveemerged and endangered public health, including the severe acuterespiratory syndrome coronavirus (SARS CoV), Middle East respiratorysyndrome CoV (MERS-CoV), and SARS-CoV-2. The SARS-CoV-2 pandemic hasnecessitated the discovery of new therapeutics to combat the increasingnumber of infected humans. While a large number of drug repurposingstudies have been conducted, the need for more and better therapeuticoptions for treating SARS-CoV-2 remains.

Thus, anti-SARS-CoV-2 fusion peptides solving the aforementionedproblems is desired.

SUMMARY

The anti-SARS-CoV-2 fusion peptides include a set of peptides designedby modification or mutation of a wild type SARS-CoV-2 fusion protein.The anti-SARS-CoV-2 fusion peptides are capable of inhibition ofSARS-CoV-2 infection in cells and may be used to prevent and/or treatSARS-CoV-2 infection in a subject in need thereof. The anti-SARS-CoV-2fusion peptides may prevent membrane-mediated viral entry,endocytosis-mediated viral entry, or prevent both membrane-mediatedviral entry and endocytosis-mediated viral entry. The anti-SARS-CoV-2fusion peptides may also be used as reagents for SARS-CoV-2 inhibitionassays as a standard or as reference inhibitors.

In an embodiment, the anti-SARS-CoV-2 fusion peptides are 39-mer aminoacid sequences including at least one mutation of the wild typeSARS-CoV-2 Heptad Repeat Doman (HR2) sequence. In a further embodiment,the anti-SARS-CoV-2 fusion peptides may be 39-mer amino acid sequencesincluding 1, 2, 3, 4, 5, or 6 mutations of the wild type SARS-CoV-2 HR2sequence.

An embodiment of the present subject matter is directed to apharmaceutical composition including one or more of the anti-SARS-CoV-2fusion peptides and a pharmaceutically acceptable carrier.

An embodiment of the present subject matter is directed to a method ofmaking a pharmaceutical composition including mixing one or more of theanti-SARS-CoV-2 fusion peptides under sterile conditions with apharmaceutically acceptable carrier and preservatives, buffers, orpropellants to create the pharmaceutical composition; and providing thepharmaceutical composition in a form suitable for daily, weekly, ormonthly administration.

An embodiment of the present subject matter is directed to compositionsincluding one or more of the anti-SARS-CoV-2 fusion peptides and one ormore expression systems. The expression system may be a viral basedexpression system, a plasmid-based expression system, or any otherexpression system suitable for causing or enhancing expression of theanti-SARS-CoV-2 fusion peptides in a bacterium, yeast, or mammaliancell. The expression system may include a promoter sequence and DNA orRNA encoding one or more of the anti-SARS-CoV-2 fusion peptides.

An embodiment of the present subject matter is directed to methods ofinhibiting SARS-CoV-2 infection, preventing SARS-CoV-2 transmission,and/or treating a SARS-CoV-2 infection, including administering to asubject in need thereof a therapeutically effective amount of apharmaceutical composition according to the present subject matter. In afurther embodiment, the methods of inhibiting SARS-CoV-2 infection mayinclude preventing SARS-CoV-2 infection of a cell.

An embodiment of the present subject matter is directed to methods ofusing the anti-SARS-CoV-2 fusion peptides as reference agents toevaluate inhibition by other candidates against SARS-CoV-2. Thesemethods may include using the SARS-CoV-2 fusion peptides as referenceagents in Cell-Cell Fusion Assays, Viral Plaque Formation Assays, ViralRNA Quantitation Assays, or the like.

These and other features of the present subject matter will becomereadily apparent upon further review of the following specification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a graph of the effect of the anti-SARS-CoV-2 fusionpeptides on SARS-CoV-2 S-mediated membrane fusion. The graph depicts theeffect of each peptide on the co-culture fusion assay using DSP as areporter. Peptides were tested at different concentrations, andadditional proteins other than reporters (DSPs) transduced into theeffector and target cells are indicated below the graph. The relativecell fusion was represented as the DSP value (RL activity measured inRLU) normalized to that of the control assay with DMSO alone. (*:p<0.05, **: p<0.01).

FIG. 2 depicts a graph of the effect of anti-SARS-CoV-2 fusion peptideson SARS-CoV-2 S-mediated viral infection of Calu-3 cells with SARS-CoV-2S pseudotyped VSV viral particles. The relative infectivity wasrepresented as the RLU normalized to that of the control assay with DMSOalone. (*: p<0.05, **: p<0.01).

FIG. 3A depicts a graph of the effect of anti-SARS-CoV-2 fusion peptideson TMPRSS2-independent viral infection (VeroE6 cells). The relativeinfectivity was represented as the RLU normalized to that of the controlassay with DMSO alone.

FIG. 3B depicts a graph of the effect of anti-SARS-CoV-2 fusion peptideson TMPRSS2-dependent viral infection (VeroE6-TMPRSS2 cells withSARS-CoV-2 s pseudotyped VSV viral particles. The relative infectivitywas represented as the RLU normalized to that of the control assay withDMSO alone.

FIG. 4 depicts a graph of the effect of anti-SARS-CoV-2 fusion peptideson SARS-CoV-2 infection in Calu-3 cells. Calu-3 cells were challengedwith SARS-CoV-2 at an MOI of 0.01 in the presence of the peptides at theindicated doses. The amount of internalized viral RNA was quantified byreal-time PCR at 24 h after infection.

FIGS. 5A-5B depict 5(A) Vero E6 cells infected with SARS-CoV-2 whereSARS-CoV-2 was incubated with each peptide prior to infection (prior toSARS-CoV-2 infection, SARS-CoV-2 was incubated with each peptide (10 μM)for 30 min at 37° C. and then added to Vero E6 cells and each well wasoverlaid with DMEM/F12 containing 2% Oxoid agar and TPCK (1μg/mL)-treated trypsin, cultured for 3 days, stained with crystalviolet, and then plaques were counted); and 5(B) a graph showing theeffect of anti-SARS-CoV-2 fusion peptides on SARS-CoV-2 infection.

FIGS. 5C-5D depict 5(C) Vero E6 cells infected with SARS-CoV-2 whereSARS-CoV-2 was incubated with peptide #125 (SEQ ID NO: 5) (prior toinfection SARS-CoV-2 was pre-incubated with three-fold serially diluted#125 peptide (SEQ ID NO: 5) (n=3) for 30 min at 37° C., the vero E6cells were infected with the mixture of the virus and peptide, incubatedfor 3 days in DMEM/F12 containing 2% Oxoid agar and TPCK (1μg/mL)-treated trypsin, each well was stained with crystal violet, andthen plaques were counted; and 5(D) a graph of the inhibitory effect of#125 peptide (SEQ ID. NO: 5) on SARS-CoV-2 infection in Vero E6 cells.

Similar reference characters denote corresponding features consistentlythroughout the attached drawings.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

An anti-SARS-CoV-2 fusion peptide include can be synthesized bymodification or mutation of a wild type SARS-CoV-2 fusion protein. Thepresent teachings are directed to a plurality of anti-SARS-CoV-2 fusionpeptides. The anti-SARS-CoV-2 fusion peptides are capable of inhibitionof SARS-CoV-2 infection in cells and may be used to prevent and/or treatSARS-CoV-2 infection in a subject in need thereof. The anti-SARS-CoV-2fusion peptides may prevent membrane-mediated viral entry,endocytosis-mediated viral entry, or prevent both membrane-mediatedviral entry and endocytosis-mediated viral entry. The anti-SARS-CoV-2fusion peptides may also be used as reagents for SARS-CoV-2 inhibitionassays as a standard or as reference inhibitors.

In an embodiment, the anti-SARS-CoV-2 fusion peptide includes a 39-meramino acid sequence including at least one mutation of the wild typeSARS-CoV-2 Heptad Repeat Doman (HR2) sequence. In a further embodiment,the anti-SARS-CoV-2 fusion peptide may include a 39-mer amino acidsequences including 1, 2, 3, 4, 5, or 6 mutations of the wild typeSARS-CoV-2 HR2 sequence.

Throughout this application, the term “about” may be used to indicatethat a value includes the standard deviation of error for thecomposition, device or method being employed to determine the value.

The use of the term “or” in the specification and claim(s) is used tomean “and/or” unless explicitly indicated to refer to alternatives onlyor the alternatives are mutually exclusive, although the disclosuresupports a definition that refers to only alternatives and “and/or.”

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, un-recitedelements or method steps. In certain cases, the term “comprising” may bereplaced with “consisting essentially of” or “consisting of.”

The use of the word “a” or “an” when used herein in conjunction with theterm “comprising” in the claims and/or the specification may mean “one,”but it is also consistent with the meaning of “one or more,” “at leastone,” and “one or more than one.”

The phrase “pharmaceutically acceptable,” as used herein, refers tomolecular entities and compositions that do not produce an allergic orsimilar untoward reaction when administered to a human.

The term “subject,” as used herein, means a mammal, including but notlimited to a human being.

As used herein, the term “providing” an agent is used to include“administering” the agent to a subject.

As used herein, a “carrier” includes any and all solvents, dispersionmedia, vehicles, coatings, diluents, isotonic and absorption delayingagents, buffers, carrier solutions, suspensions, colloids, excipients,and the like.

An embodiment of the present subject matter is directed to apharmaceutical composition comprising one or more of the anti-SARS-CoV-2fusion peptides and a pharmaceutically acceptable carrier.

An embodiment of the present subject matter is directed to a method ofmaking a pharmaceutical composition including mixing one or more of theanti-SARS-CoV-2 fusion peptides with a pharmaceutically acceptablecarrier. For example, the method of making a pharmaceutical compositioncan include mixing an anti-SARS-CoV-2 fusion peptide under sterileconditions with a pharmaceutically acceptable carrier withpreservatives, buffers, and/or propellants to create the pharmaceuticalcomposition.

An embodiment of the present subject matter is directed to apharmaceutical composition including one or more of the anti-SARS-CoV-2fusion peptides. To prepare the pharmaceutical composition, one or moreof the anti-SARS-CoV-2 fusion peptides, as the active ingredient, isintimately admixed with a pharmaceutically acceptable carrier accordingto conventional pharmaceutical compounding techniques. Carriers areinert pharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorings, sweeteners, preservatives,dyes, and coatings. In preparing compositions in oral dosage form, anyof the pharmaceutical carriers known in the art may be employed. Forexample, for liquid oral preparations, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like. Further, for solid oral preparations,suitable carriers and additives include starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents, and thelike.

The present compositions can be in unit dosage forms such as tablets,pills, capsules, powders, granules, ointments, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampules, auto-injector devices or suppositories, for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. One or more of the anti-SARS-CoV-2 fusionpeptides can be mixed under sterile conditions with a pharmaceuticallyacceptable carrier and, if required, any needed preservatives, buffers,or propellants. The composition can be presented in a form suitable fordaily, weekly, or monthly administration. The pharmaceuticalcompositions herein will contain, per dosage unit, e.g., tablet,capsule, powder, injection, teaspoonful, suppository and the like, anamount of the active ingredient necessary to deliver an effective dose.A therapeutically effective amount of an anti-SARS-CoV-2 fusion peptidesor an amount effective to treat a disease, such as a coronavirusinfection, may be determined initially from the Examples describedherein and adjusted for specific targeted diseases using routinemethods.

An embodiment of the present subject matter is directed to compositionsincluding one or more of the anti-SARS-CoV-2 fusion peptides and one ormore expression systems. The expression system may be a viral basedexpression system, a plasmid-based expression system, or any otherexpression system suitable for causing or enhancing expression of theanti-SARS-CoV-2 fusion peptides in a bacterium, yeast, or mammaliancell. The expression system may include a promoter sequence and DNA orRNA encoding one or more of the anti-SARS-CoV-2 fusion peptides.

An embodiment of the present subject matter is directed to methods ofusing the anti-SARS-CoV-2 fusion peptides as reference agents toevaluate inhibition by other candidates against SARS-CoV-2. Thesemethods may include using the anti-SARS-CoV-2 fusion peptides asreference agents in Cell-Cell Fusion Assays, Viral Plaque FormationAssays, Viral RNA Quantitation Assays, or the like.

The anti-SARS-CoV-2 fusion peptides can be administered to a subject inneed thereof. In an embodiment, the anti-SARS-CoV-2 fusion peptides canbe administered to a subject in need thereof to inhibit SARS-CoV-2infection, prevent SARS-CoV-2 transmission, and/or treat a SARS-CoV-2infection.

An embodiment of the present subject matter is directed to a method ofinhibiting SARS-CoV-2 infection, preventing SARS-CoV-2 transmission,and/or treating a SARS-CoV-2 infection, comprising administering to asubject in need thereof a therapeutically effective amount of thepharmaceutical composition according to the present subject matter.

The anti-SARS-CoV-2 fusion peptides or pharmaceutical compositionsthereof can be administered to a subject by any suitable route. Forexample, the compositions can be administered nasally, rectally,intracisternally, intraperitoneally, transdermally (as by powders,ointments, or drops), and/or parenterally. As used herein, “parenteral”administration refers to modes of administration other than through thegastrointestinal tract, which include intravenous, intramuscular,intraperitoneal, intrasternal, intramammary, intraocular,intrapulmonary, intrathecal, subcutaneous and intraarticular injectionand infusion. Surgical implantation may also be contemplated, including,for example, embedding a composition of the disclosure in the body suchas, for example, in a tissue, in the abdominal cavity, under the spleniccapsule, brain, or in the cornea.

Accordingly, the route of administration can include intranasaladministration, oral administration, inhalation administration,subcutaneous administration, transdermal administration, intradermaladministration, intra-arterial administration with or without occlusion,intracranial administration, intraventricular administration,intravenous administration, buccal administration, intraperitonealadministration, intraocular administration, intramuscularadministration, implantation administration, topical administration,intratumor administration, and/or central venous administration.

The viral CoV genome encodes four structural proteins: spike (S),membrane (M), envelope (E), and nucleocapsid (N). Viral membrane fusionis an essential step of virus replication, which is accomplished by theviral spike and leads to the fusion of the viral and cell membranes. TheCoV S protein is composed of two subunits, S1 and S2. S1 binds the hostcell ACE2 receptor. Cleavage of S1 by host cell proteases exposes ahighly hydrophobic membrane-binding domain of the S2 subunit. The S2subunit contains two domains, heptad repeat domain 1 (HR1) and heptadrepeat domain 2 (HR2). HR1 forms a homotrimer exposing three hydrophobicpockets on its surface, which host the HR2 domain during the activefusion process. An HR domain is composed of tandem repeat motifs ofseven residues (named a-g). Of the seven residues, the first (a) andfourth (d) are predominantly hydrophobic or bulky.

The anti-SARS-CoV-2 fusion peptides are designed by modification ormutation of a surface structure protein of SARS-CoV-2 in the virus S2spike region. The heptad repeat regions (HR1 and HR2) of S2 interact tohelp in fusion of SARS-CoV-2 with cell membranes. The anti-SARS-CoV-2fusion peptides S2 HR2 derivatives were optimized to interfere with theproper mechanism of HR1-HR2 interactions.

Optimization included in silico modeling of potential mutations in HR2and the selection of peptides with the highest changes in affinity andstability. (See Example 1, Table 1, for a list of tested mutations) Themutations that gave rise to the selected peptides were then combined ina further in silico energy maturation study. The resultinganti-SARS-CoV-2 fusion peptides possessed up to six mutations comparedto the wild type sequence. (See Example 2, Table 2, for examples ofpossible combinations of mutations)

In an embodiment, the anti-SARS-CoV-2 peptide includes peptide #121 (SEQID NO. 2: HVLGDISGINASVVQIQKEIDRLNEVAKNLHESLIYLQE), peptide #122 (SEQ IDNO. 3: VDLGDISGIRAMVVRIQKEMRLNEVAKNLNESLIDLQE), peptide #123 (SEQ ID NO.4: LRLGDISGIRARVVRIQKEIHRLNEVAKNLNESLIDLQN), or peptide #125 (SEQ ID NO.5: HRLRQIRGIRARVVQIQKEIWRLNEVAKLLNESLIYLQE).

The following examples illustrate the present subject matter.

Example 1 Mutations of HR2

HR2 amino acid mutations were tested in silico to find the most potentcandidate that can bind potently with HR1. (Schrodinger Suite 2020, NY,USA). Protein structures were optimized using the protein preparationwizard, followed by energy minimization and mutation. To ensurereproducibility, the experiment was repeated three times. For thispurpose, stepwise mutations were carried out as follows.

Every residue in HR2 was mutated to all of the potential candidates,comprising the twenty known essential amino acids. The mutations wereevaluated based on the changes in binding free energy as well as thesolvated peptide stability. Table 1 shows the results of initial singleamino acids mutations. In Table 1, the Residue # is listed as R #, theoriginal amino acid is listed as “WT”, and the mutated amino acid islisted as “MUT”. The “Δ Affinity” implies the changes in binding energy(Kcal/mol) after each mutation. The “Δ Stability” implies the changes insolvation stability after each mutation.

TABLE 1 Single Amino Acid Mutations in HR2 R # WT MUT Δ Aff. Δ Stab.1164 VAL ILE 0 5.26 1164 VAL GLN −0.08 −44 1164 VAL GLY −0.19 25.92 1164VAL GLU 0.94 −22.5 1164 VAL CYS 0.2 −2.67 1164 VAL ASP 1.77 −25.7 1164VAL SER −0.13 0.85 1164 VAL LYS −0.74 −6.68 1164 VAL PRO −0.29 42.531164 VAL HIE 0.3 −9.16 1164 VAL ASN −0.1 −36.71 1164 VAL HIP −1.37−11.26 1164 VAL THR −0.14 −10.93 1164 VAL HID −0.04 −11.42 1164 VAL TRP0.23 −7.29 1164 VAL PHE 0.07 0.13 1164 VAL ALA −0.05 4.21 1164 VAL MET−0.11 −6.33 1164 VAL LEU 0.02 9.25 1164 VAL ARG 1.75 −35.88 1164 VAL TYR0.06 −9.2 1164 VAL ILE 0 5.26 1164 VAL GLN −0.08 −44 1164 VAL GLY −0.1925.92 1164 VAL GLU 0.94 −22.5 1164 VAL CYS 0.2 −2.67 1164 VAL ASP 1.77−25.7 1164 VAL SER −0.13 0.85 1164 VAL LYS −0.74 −6.68 1164 VAL PRO−0.29 42.53 1164 VAL HIE 0.3 −9.16 1164 VAL ASN −0.1 −36.71 1164 VAL HIP−1.37 −11.26 1164 VAL THR −0.14 −10.93 1164 VAL HID −0.04 −11.42 1164VAL TRP 0.23 −7.29 1164 VAL PHE 0.07 0.13 1164 VAL ALA −0.05 4.21 1164VAL MET −0.11 −6.33 1164 VAL LEU 0.02 9.25 1164 VAL ARG 1.75 −35.88 1164VAL TYR 0.06 −9.2 1164 VAL ILL 0 5.26 1164 VAL GLN −0.08 −44 1164 VALGLY −0.19 25.92 1164 VAL GLU 0.94 −22.5 1164 VAL CYS 0.2 −2.67 1164 VALASP 1.77 −25.7 1164 VAL SER −0.13 0.85 1164 VAL LYS −0.74 −6.68 1164 VALPRO −0.29 42.53 1164 VAL HIE 0.3 −9.16 1164 VAL ASN −0.1 −36.71 1164 VALHIP −1.37 −11.26 1164 VAL THR −0.14 −10.93 1164 VAL HID −0.04 −11.421164 VAL TRP 0.23 −7.29 1164 VAL PHE 0.07 0.13 1164 VAL ALA −0.05 4.211164 VAL MET −0.11 −6.33 1164 VAL LEU 0.02 9.25 1164 VAL ARG 1.75 −35.881164 VAL TYR 0.06 −9.2 1164 VAL ILE 0 5.26 1164 VAL GLN −0.08 −44 1164VAL GLY −0.19 25.92 1164 VAL GLU 0.94 −22.5 1164 VAL CYS 0.2 −2.67 1164VAL ASP 1.77 −25.7 1164 VAL SER −0.13 0.85 1164 VAL LYS −0.74 −6.69 1164VAL PRO −0.29 42.53 1164 VAL HIE 0.3 −9.16 1164 VAL ASN −0.1 −36.71 1164VAL HIP −1.37 −11.26 1164 VAL THR −0.14 −10.93 1164 VAL HID −0.04 −11.421164 VAL TRP 0.23 −7.29 1164 VAL PHE 0.07 0.13 1164 VAL ALA −0.05 4.211164 VAL MET −0.11 −6.33 1164 VAL LEU 0.02 9.25 1164 VAL ARG 1.75 −35.881164 VAL TYR 0.06 −9.2 1165 ASP ILE −0.76 −5.37 1165 ASP GLN −0.44 −4.151165 ASP GLY −0.74 −2.59 1165 ASP GLU 0.04 −3.36 1165 ASP CYS −0.79−3.24 1165 ASP SER −0.77 −4.57 1165 ASP LYS −1.34 −1.03 1165 ASP PRO−0.88 11.78 1165 ASP HIE −0.64 −5.74 1165 ASP ASN −0.73 −0.83 1165 ASPHIP −1.45 −6.16 1165 ASP VAL −0.75 −5.22 1165 ASP THR −0.78 −6.62 1165ASP HID −0.73 −2.07 1165 ASP TRP −0.68 −2.53 1165 ASP PHE −0.67 −0.931165 ASP ALA −0.76 −0.76 1165 ASP MET −0.82 −4.79 1165 ASP LEU −0.79−4.7 1165 ASP ARG −1.48 −3.22 1165 ASP TYR −0.41 −1.39 1165 ASP ILE−0.76 −5.37 1165 ASP GLN −0.44 −4.15 1165 ASP GLY −0.74 −2.59 1165 ASPGLU 0.04 −3.36 1165 ASP CYS −0.79 −3.24 1165 ASP SER −0.77 −4.57 1165ASP LYS −1.34 −1.03 1165 ASP PRO −0.88 11.78 1165 ASP HIE −0.64 −5.741165 ASP ASN −0.73 −0.83 1165 ASP HIP −1.45 −6.16 1165 ASP VAL −0.75−5.22 1165 ASP THR −0.78 −6.62 1165 ASP HID −0.73 −2.07 1165 ASP TRP−0.68 −2.53 1165 ASP PHE −0.67 −0.93 1165 ASP ALA −0.76 −0.76 1165 ASPMET −0.82 −4.79 1165 ASP LEU −0.79 −4.7 1165 ASP ARG −1.48 −3.22 1165ASP TYR −0.41 −1.39 1166 LEU ILE 0.02 0.71 1166 LEU GLN 0.43 9.37 1166LEU GLY 0 19.92 1166 LEU GLU 2.3 16.54 1166 LEU CYS 0.02 14.41 1166 LEUASP 1.68 20.42 1166 LEU SER 0.22 16.78 1166 LEU LYS −1.97 23.62 1166 LEUPRO −0.11 25.93 1166 LEU HIE 0.03 15.42 1166 LEU ASN −0.27 14.1 1166 LEUHIP −1.25 7.74 1166 LEU VAL 0.04 5.46 1166 LEU THR 0.17 10.98 1166 LEUHID 0.33 9.07 1166 LEU TRP 0.3 5.39 1166 LEU PHE 0.14 5.29 1166 LEU ALA0 17.28 1166 LEU MET 0.06 −7.89 1166 LEU ARG −0.49 7.55 1166 LEU TYR0.17 5.15 1166 LEU ILE 0.02 0.71 1166 LEU GLN 0.43 9.37 1166 LEU GLY 019.92 1166 LEU GLU 2.3 16.54 1166 LEU CYS 0.02 14.41 1166 LEU ASP 1.6820.42 1166 LEU SER 0.22 16.78 1166 LEU LYS −1.97 23.62 1166 LEU PRO−0.11 25.93 1166 LEU HIE 0.03 15.42 1166 LEU ASN −0.27 14.1 1166 LEU HIP−1.25 7.74 1166 LEU VAL 0.04 5.46 1166 LEU THR 0.17 10.98 1166 LEU HID0.33 9.07 1166 LEU TRP 0.3 5.39 1166 LEU PHE 0.14 5.29 1166 LEU ALA 017.28 1166 LEU MET 0.06 −7.89 1166 LEU ARG −0.49 7.55 1166 LEU TYR 0.175.15 1167 GLY ILE −1.06 6.91 1167 GLY GLN −0.66 3.47 1167 GLY GLU −0.184.83 1167 GLY CYS −0.17 5.7 1167 GLY ASP 0.73 7.42 1167 GLY SER −0.086.04 1167 GLY LYS −0.39 6.24 1167 GLY PRO −0.03 46.27 1167 GLY HIE 1.035.26 1167 GLY ASN 0.36 4.09 1167 GLY HIP 1.31 −2.02 1167 GLY VAL −0.7614.01 1167 GLY THR −0.84 4.03 1167 GLY HID −0.08 −1.79 1167 GLY TRP 0.123.58 1167 GLY PHE −4.27 2.42 1167 GLY ALA −0.07 3.06 1167 GLY MET −1.131.94 1167 GLY LEU −1.03 −1.79 1167 GLY ARG −0.65 −2.59 1167 GLY TYR−0.03 2.72 1167 GLY ILE −1.06 6.91 1167 GLY GLN −0.66 3.46 1167 GLY GLU−0.18 4.85 1167 GLY CYS −0.17 5.7 1167 GLY ASP 0.73 7.42 1167 GLY SER−0.08 6.04 1167 GLY LYS −0.39 6.24 1167 GLY PRO −0.03 46.27 1167 GLY HIE1.03 5.26 1167 GLY ASN 0.36 4.09 1167 GLY HIP 1.31 −2.01 1167 GLY VAL−0.76 14.01 1167 GLY THR −0.84 4.03 1167 GLY HID −0.08 −1.79 1167 GLYTRP 0.12 3.58 1167 GLY PHE −4.27 2.42 1167 GLY ALA −0.07 3.06 1167 GLYMET −1.13 1.94 1167 GLY LEU −1.03 −1.79 1167 GLY ARG −0.65 −2.56 1167GLY TYR −0.03 2.72 1168 ASP ILE −0.68 −0.71 1168 ASP GLN −1.89 −8.181168 ASP GLY −0.43 3.32 1168 ASP GLU 0.17 −6.06 1168 ASP CYS −0.68 0.561168 ASP SER −0.53 −0.15 1168 ASP LYS −0.48 4.75 1168 ASP PRO −0.63 2.821168 ASP HIE −0.41 2.5 1168 ASP ASN −0.58 −5.8 1168 ASP HIP −0.75 −1.651168 ASP VAL −0.47 0.63 1168 ASP THR −0.55 −0.72 1168 ASP HID −0.4 0.471168 ASP TRP −0.26 0.29 1168 ASP PHE 0.05 3.8 1168 ASP ALA −0.47 2.091168 ASP MET −0.78 −7.36 1168 ASP LEU −0.85 −0.12 1168 ASP ARG −1.26−5.35 1168 ASP TYR −2.01 1.41 1168 ASP ILE −0.68 −0.71 1168 ASP GLN−1.89 −8.18 1168 ASP GLY −0.43 3.32 1168 ASP GLU 0.17 −6.06 1168 ASP CYS−0.68 0.56 1168 ASP SER −0.53 −0.15 1168 ASP LYS −0.48 4.75 1168 ASP PRO−0.63 2.82 1168 ASP HIE −0.41 2.5 1168 ASP ASN −0.58 −5.8 1168 ASP HIP−0.75 −1.65 1168 ASP VAL −0.47 0.63 1168 ASP THR −0.55 −0.72 1168 ASPHID −0.4 0.47 1168 ASP TRP −0.24 0.97 1168 ASP PHE 0.05 3.8 1168 ASP ALA−0.47 2.09 1168 ASP MET −0.78 −7.36 1168 ASP LEU −0.85 −0.12 1168 ASPARG −1.26 −5.35 1168 ASP TYR −2.06 1.41 1169 ILE GLN 0.2 8.82 1169 ILEGLY 0 22.65 1169 ILE GLU 2.74 19.63 1169 ILE CYS 0.13 14.61 1169 ILE ASP2.32 24.75 1169 ILE SER 0.1 18.59 1169 ILE LYS −2.24 29.09 1169 ILE PRO−0.11 25.54 1169 ILE HIE −0.18 10.88 1169 ILE ASN 0.12 15.84 1169 ILEHIP −1.83 7.55 1169 ILE VAL −0.01 2.67 1169 ILE THR 0.2 11.86 1169 ILEHID 0.37 5.88 1169 ILE TRP −0.09 103.59 1169 ILE PHE −0.15 0.02 1169 ILEALA 0.02 17.6 1169 ILE MET −0.02 −8.6 1169 ILE LEU −0.09 −2.84 1169 ILEARG −2.47 6.88 1169 ILE TYR −0.17 15.35 1169 ILE GLN 0.2 8.82 1169 ILEGLY 0 22.65 1169 ILE GLU 2.74 19.63 1169 ILE CYS 0.13 14.61 1169 ILE ASP2.32 24.75 1169 ILE SER 0.1 18.59 1169 ILE LYS −2.24 29.09 1169 ILE PRO−0.11 25.54 1169 ILE HIE −0.18 10.88 1169 ILE ASN 0.12 15.84 1169 ILEHIP −1.83 7.55 1169 ILE VAL −0.01 2.67 1169 ILE THR 0.2 11.86 1169 ILEHID 0.37 5.88 1169 ILE TRP −0.09 103.59 1169 ILE PHE −0.15 0.02 1169 ILEALA 0.02 17.6 1169 ILE MET −0.02 −8.6 1169 ILE LEU −0.09 −2.84 1169 ILEARG −2.47 6.88 1169 ILE TYR −0.17 15.35 1170 SER ILE 0.21 −0.6 1170 SERGLN 0.38 1.65 1170 SER GLY −0.02 2.5 1170 SER GLU 3.9 5.43 1170 SER CYS−0.02 0.02 1170 SER ASP 0.86 9.19 1170 SER LYS −0.53 1.83 1170 SER PRO−0.03 86.83 1170 SER HIE 0.65 1.71 1170 SER ASN −0.08 0.26 1170 SER HIP−0.71 −3.29 1170 SER VAL 0.09 0.57 1170 SER THR −0.02 0.27 1170 SER HID−0.21 −3.32 1170 SER TRP 0.3 3.53 1170 SER PHE 0.06 2.19 1170 SER ALA0.02 0.99 1170 SER MET 0.02 −3.21 1170 SER LEU 0.14 −3.56 1170 SER ARG−0.65 −5.84 1170 SER TYR 0.91 2.03 1170 SER ILE 0.21 −0.6 1170 SER GLN0.38 1.65 1170 SER GLY −0.02 2.5 1170 SER GLU 3.9 5.43 1170 SER CYS−0.02 0.02 1170 SER ASP 0.86 9.19 1170 SER LYS −0.53 1.83 1170 SER PRO−0.03 86.83 1170 SER HIE 0.65 1.71 1170 SER ASN −0.08 0.26 1170 SER HIP−0.71 −3.29 1170 SER VAL 0.09 0.57 1170 SER THR −0.02 0.27 1170 SER HID−0.21 −3.32 1170 SER TRP 0.3 3.53 1170 SER PHE 0.06 2.19 1170 SER ALA0.02 0.99 1170 SER MET 0.02 −3.21 1170 SER LEU 0.14 −3.56 1170 SER ARG−0.65 −5.86 1170 SER TYR 0.91 2.03 1171 GLY ILE −0.02 1.8 1171 GLY GLN0.37 −1.35 1171 GLY GLU 0.53 3.45 1171 GLY CYS −0.05 1.27 1171 GLY ASP0.54 9.71 1171 GLY SER −0.04 3.33 1171 GLY LYS 10.74 3.6 1171 GLY PRO−0.56 30.26 1171 GLY HIE 1.64 2.79 1171 GLY ASN 0.35 4.89 1171 GLY HIP1.71 0.43 1171 GLY VAL −0.01 1.6 1171 GLY THR −0.04 −5.02 1171 GLY HID−0.02 0.49 1171 GLY TRP −2.29 7.51 1171 GLY PHE −0.03 5.38 1171 GLY ALA−0.02 2.78 1171 GLY MET 0.12 −0.07 1171 GLY LEU −0.02 1.68 1171 GLY ARG−0.65 −5.55 1171 GLY TYR −0.96 5.77 1171 GLY ILE −0.02 1.8 1171 GLY GLN0.37 −1.35 1171 GLY GLU 0.52 3.49 1171 GLY CYS −0.05 1.27 1171 GLY ASP0.54 9.71 1171 GLY SER −0.04 3.33 1171 GLY LYS 10.75 3.6 1171 GLY PRO−0.56 30.26 1171 GLY HIE 1.64 2.8 1171 GLY ASN 0.35 4.89 1171 GLY HIP1.7 0.37 1171 GLY VAL −0.01 1.6 1171 GLY THR −0.04 −5.02 1171 GLY HID−0.02 0.49 1171 GLY TRP −2.33 7.56 1171 GLY PHE −0.02 5.4 1171 GLY ALA−0.02 2.78 1171 GLY MET 0.12 −0.06 1171 GLY LEU −0.03 1.68 1171 GLY ARG−0.65 −5.53 1171 GLY TYR −0.96 5.77 1171 GLY ILE −0.02 1.8 1171 GLY GLN0.37 −1.35 1171 GLY GLU 0.52 3.49 1171 GLY CYS −0.05 1.27 1171 GLY ASP0.54 9.71 1171 GLY SER −0.04 3.33 1171 GLY LYS 10.75 3.6 1171 GLY PRO−0.56 30.26 1171 GLY HIE 1.64 2.8 1171 GLY ASN 0.35 4.89 1171 GLY HIP1.7 0.37 1171 GLY VAL −0.01 1.6 1171 GLY THR −0.04 −5.02 1171 GLY HID−0.02 0.49 1171 GLY TRP −2.35 7.56 1171 GLY PHE −0.02 5.4 1171 GLY ALA−0.02 2.78 1171 GLY MET 0.12 −0.06 1171 GLY LEU −0.02 1.68 1171 GLY ARG−0.65 −5.47 1171 GLY TYR −0.96 5.77 1172 ILE GLN −0.14 7.07 1172 ILE GLY−0.18 20.21 1172 ILE GLU 0.76 10.38 1172 ILE CYS −0.04 14.19 1172 ILEASP 1.14 23.26 1172 ILE SER −0.12 18.65 1172 ILE LYS −0.84 20.64 1172ILE PRO −0.04 42.28 1172 ILE HIE 0 7.2 1172 ILE ASN −0.36 14.28 1172 ILEHIP −0.99 5.54 1172 ILE VAL 0 5.18 1172 ILE THR 0.1 9.41 1172 ILE HID0.3 11.9 1172 ILE TRP 0.07 5.39 1172 ILE PHE −0.09 9.7 1172 ILE ALA−0.12 15.81 1172 ILE MET 0.42 −4.21 1172 ILE LEU −0.03 4.13 1172 ILE ARG−1.05 2.62 1172 ILE TYR −0.18 10.32 1172 ILE GLN −0.14 7.07 1172 ILE GLY−0.18 20.21 1172 ILE GLU 0.76 10.38 1172 ILE CYS −0.04 14.19 1172 ILEASP 1.14 23.26 1172 ILE SER −0.12 18.65 1172 ILE LYS −0.84 20.64 1172ILE PRO −0.04 42.28 1172 ILE HIE 0 7.2 1172 ILE ASN −0.36 14.28 1172 ILEHIP −0.99 5.54 1172 ILE VAL 0 5.18 1172 ILE THR 0.1 9.41 1172 ILE HID0.3 11.9 1172 ILE TRP 0.07 5.39 1172 ILE PHE −0.09 9.7 1172 ILE ALA−0.12 15.81 1172 ILE MET 0.42 −4.21 1172 ILE LEU −0.03 4.13 1172 ILE ARG−1.05 2.62 1172 ILE TYR −0.18 10.32 1173 ASN ILE 0 −4.92 1173 ASN GLN0.01 −5.55 1173 ASN GLY −0.05 −3.06 1173 ASN GLU 0.88 −0.26 1173 ASN CYS−0.13 −4.72 1173 ASN ASP 0.72 0.24 1173 ASN SER −0.12 −2.74 1173 ASN LYS−0.58 −3.68 1173 ASN PRO −0.08 15.96 1173 ASN HIE 0.17 −3.87 1173 ASNHIP −1.09 −8.64 1173 ASN VAL −0.07 −3.8 1173 ASN THR −0.11 −3.65 1173ASN HID 0.04 −7.6 1173 ASN TRP 0.36 −6.38 1173 ASN PHE 0.39 −6.17 1173ASN ALA −0.08 −3.06 1173 ASN MET −0.08 −8.04 1173 ASN LEU 0.06 −6.341173 ASN ARG −0.79 −12.67 1173 ASN TYR 0.61 −6.77 1173 ASN ILE 0 −4.921173 ASN GLN 0.01 −5.55 1173 ASN GLY −0.05 −3.06 1173 ASN GLU 0.88 −0.261173 ASN CYS −0.13 −4.72 1173 ASN ASP 0.72 0.24 1173 ASN SER −0.12 −2.741173 ASN LYS −0.58 −3.68 1173 ASN PRO −0.08 15.96 1173 ASN HIE 0.17−3.87 1173 ASN HIP −1.09 −8.64 1173 ASN VAL −0.07 −3.8 1173 ASN THR−0.11 −3.65 1173 ASN HID 0.04 −7.6 1173 ASN TRP 0.36 −6.38 1173 ASN PHE0.39 −6.17 1173 ASN ALA −0.08 −3.06 1173 ASN MET −0.08 −8.04 1173 ASNLEU 0.06 −6.34 1173 ASN ARG −0.79 −12.67 1173 ASN TYR 0.61 −6.77 1174ALA ILE 0.03 1.77 1174 ALA GLN 0.6 14.37 1174 ALA GLY −0.06 7.02 1174ALA GLU 14.4 20.32 1174 ALA CYS −0.1 7.58 1174 ALA ASP 2.58 30.89 1174ALA SER 0.25 3.57 1174 ALA LYS −1.42 44.97 1174 ALA PRO 0.03 24.59 1174ALA HIE 1.01 98.29 1174 ALA ASN −13.68 32.46 1174 ALA HIP −1.42 95.281174 ALA VAL −0.18 22.44 1174 ALA THR −0.9 14.58 1174 ALA HID 1.13 95.861174 ALA TRP −0.55 57.47 1174 ALA PHE 0.27 68.41 1174 ALA MET −2.6 17.321174 ALA LEU −0.85 31.41 1174 ALA ARG −2.47 13.19 1174 ALA TYR 0.0472.77 1174 ALA ILE 0.03 1.77 1174 ALA GLN 0.6 14.37 1174 ALA GLY −0.067.02 1174 ALA GLU 14.4 20.32 1174 ALA CYS −0.1 7.58 1174 ALA ASP 2.5830.89 1174 ALA SER 0.25 3.57 1174 ALA LYS −1.42 44.97 1174 ALA PRO 0.0324.59 1174 ALA HIE 1.01 98.29 1174 ALA ASN −13.68 32.46 1174 ALA HIP−1.42 95.28 1174 ALA VAL −0.18 22.44 1174 ALA THR −0.9 14.58 1174 ALAHID 1.13 95.86 1174 ALA TRP −0.55 57.47 1174 ALA PHE 0.27 68.41 1174 ALAMET −2.6 17.32 1174 ALA LEU −0.85 31.41 1174 ALA ARG −2.47 13.19 1174ALA TYR 0.04 72.77 1174 ALA ILE 0.03 1.77 1174 ALA GLN 0.6 14.37 1174ALA GLY −0.06 7.02 1174 ALA GLU 14.4 20.32 1174 ALA CYS −0.1 7.58 1174ALA ASP 2.58 30.89 1174 ALA SER 0.25 3.57 1174 ALA LYS −1.42 44.97 1174ALA PRO 0.03 24.59 1174 ALA HIE 1.01 98.29 1174 ALA ASN −13.68 32.461174 ALA HIP −1.42 95.28 1174 ALA VAL −0.18 22.44 1174 ALA THR −0.914.58 1174 ALA HID 1.13 95.86 1174 ALA TRP −0.55 57.47 1174 ALA PHE 0.2768.41 1174 ALA MET −2.6 17.32 1174 ALA LEU −0.85 31.41 1174 ALA ARG−2.47 13.19 1174 ALA TYR 0.04 72.77 1174 ALA ILE 0.03 1.77 1174 ALA GLN0.6 14.37 1174 ALA GLY −0.06 7.02 1174 ALA GLU 14.4 20.32 1174 ALA CYS−0.1 7.58 1174 ALA ASP 2.58 30.89 1174 ALA SER 0.25 3.57 1174 ALA LYS−1.42 44.97 1174 ALA PRO 0.03 24.59 1174 ALA HIE 1.01 98.29 1174 ALA ASN−13.68 32.46 1174 ALA HIP −1.42 95.28 1174 ALA VAL −0.18 22.44 1174 ALATHR −0.9 14.58 1174 ALA HID 1.13 95.86 1174 ALA TRP −0.55 57.47 1174 ALAPHE 0.27 68.41 1174 ALA MET −2.6 17.32 1174 ALA LEU −0.85 31.41 1174 ALAARG −2.47 13.19 1174 ALA TYR 0.04 72.77 1175 SER ILE −1.05 −6.26 1175SER GLN 0.46 −9.07 1175 SER GLY 0.06 3.57 1175 SER GLU 1.47 −2.37 1175SER CYS −0.04 −1.18 1175 SER ASP 0.75 11.05 1175 SER LYS −0.04 2.21 1175SER PRO −0.86 13.52 1175 SER HIE 0.22 −1.26 1175 SER ASN 0.01 −2.11 1175SER HIP −0.16 −10.84 1175 SER VAL 0.18 −3.92 1175 SER THR 0.01 −0.961175 SER HID −0.02 −5.35 1175 SER TRP 0.46 −0.76 1175 SER PHE 0.1 −1.461175 SER ALA 0.09 0.29 1175 SER MET −0.19 −6.87 1175 SER LEU −0.32 −1.021175 SER ARG −0.32 −15.18 1175 SER TYR 0.5 −1.54 1175 SER ILE −1.05−6.26 1175 SER GLN 0.46 −9.07 1175 SER GLY 0.06 3.57 1175 SER GLU 1.47−2.37 1175 SER CYS −0.04 −1.18 1175 SER ASP 0.75 11.05 1175 SER LYS−0.04 2.21 1175 SER PRO −0.86 13.52 1175 SER HIE 0.22 −1.26 1175 SER ASN0.01 −2.11 1175 SER HIP −0.16 −10.84 1175 SER VAL 0.18 −3.92 1175 SERTHR 0.01 −0.96 1175 SER HID −0.02 −5.35 1175 SER TRP 0.46 −0.76 1175 SERPHE 0.1 −1.46 1175 SER ALA 0.09 0.29 1175 SER MET −0.19 −6.87 1175 SERLEU −0.32 −1.02 1175 SER ARG −0.32 −15.18 1175 SER TYR 0.5 −1.54 1176VAL ILE 0.03 −1.02 1176 VAL GLN −0.17 −7.89 1176 VAL GLY −0.07 5.89 1176VAL GLU 0.74 3.01 1176 VAL CYS −0.16 2.27 1176 VAL ASP 0.65 8.46 1176VAL SER −0.13 4.31 1176 VAL LYS −0.3 6.12 1176 VAL PRO −0.2 3.95 1176VAL HIE 0.09 2.65 1176 VAL ASN −0.16 −1.31 1176 VAL HIP 0.59 −3.47 1176VAL THR −0.16 −2.68 1176 VAL HID 0.21 −2.44 1176 VAL TRP 0.36 −2.36 1176VAL PHE 0.02 −5.16 1176 VAL ALA −0.05 4.25 1176 VAL MET 0.25 −7.02 1176VAL LEU 0.06 −4.5 1176 VAL ARG 2.25 −8.16 1176 VAL TYR −0.02 −9.81 1177VAL ILE −0.01 −7.9 1177 VAL GLN −0.83 10.65 1177 VAL GLY −0.08 20.161177 VAL GLU 1.59 17.13 1177 VAL CYS 0.11 8.66 1177 VAL ASP 2.03 26.851177 VAL SER −0.15 16.76 1177 VAL LYS −0.81 80.26 1177 VAL PRO −0.0240.8 1177 VAL HIE −0.06 29.21 1177 VAL ASN −0.46 13.55 1177 VAL HIP−1.78 30.06 1177 VAL THR −0.13 10.58 1177 VAL HID 0.06 30.17 1177 VALTRP 0.25 1253.69 1177 VAL PHE −0.02 60.84 1177 VAL ALA −0.06 11.87 1177VAL MET 0.1 35.52 1177 VAL LEU −0.1 3.56 1177 VAL ARG −1.97 34.38 1177VAL TYR 0.09 131.02 1178 ASN ILE 0.06 −11.1 1178 ASN GLN −3.33 −6.191178 ASN GLY 0 −1.67 1178 ASN GLU 0.31 −10.28 1178 ASN CYS −0.06 −4.231178 ASN ASP 0.51 4.63 1178 ASN SER −0.03 1.09 1178 ASN LYS 0.88 −1.691178 ASN PRO −0.17 11.73 1178 ASN HIE −0.04 −2.65 1178 ASN HIP −0.17−8.22 1178 ASN VAL 0.05 −6.27 1178 ASN THR 0.03 −5.31 1178 ASN HID 0.06−7.04 1178 ASN TRP −0.02 −9.51 1178 ASN PHE 0.08 −5.55 1178 ASN ALA−0.01 −3.08 1178 ASN MET −0.25 −6.09 1178 ASN LEU 0.11 −8.13 1178 ASNARG −0.24 −13.48 1178 ASN TYR 1.1 −5.58 1179 ILE GLN −0.14 12.9 1179 ILEGLY −0.22 31.18 1179 ILE GLU 2.55 29.78 1179 ILE CYS 0.06 19.32 1179 ILEASP 1.72 34.64 1179 ILE SER −0.03 24 1179 ILE LYS −1.76 42.49 1179 ILEPRO −0.05 57.98 1179 ILE HIE −0.12 17.6 1179 ILE ASN 0.39 22.14 1179 ILEHIP −1.3 13.33 1179 ILE VAL −0.09 8.61 1179 ILE THR 0.1 16.64 1179 ILEHID 0.69 17.98 1179 ILE TRP 0.28 206.13 1179 ILE PHE −0.02 111.62 1179ILE ALA −0.13 23.73 1179 ILE MET 0.18 −1.07 1179 ILE LEU 0.12 −1.18 1179ILE ARG −2.2 42.65 1179 ILE TYR 0.03 121.99 1180 GLN ILE −0.09 −1.671180 GLN GLY −0.07 5.4 1180 GLN GLU 0.32 3.56 1180 GLN CYS −0.12 2.011180 GLN ASP 0.36 7.27 1180 GLN SER −0.12 4.09 1180 GLN LYS −0.33 4.051180 GLN PRO −0.25 24.75 1180 GLN HIE 0.07 2.98 1180 GLN ASN −0.01 1.481180 GLN HIP −0.32 −2.08 1180 GLN VAL −0.09 1.4 1180 GLN THR −0.12 1.191180 GLN HID −0.13 −0.73 1180 GLN TRP 0.06 0.42 1180 GLN PHE 0.04 1.051180 GLN ALA −0.11 4.78 1180 GLN MET −0.06 −1.12 1180 GLN LEU −0.08−1.55 1180 GLN ARG 2.51 −3.93 1180 GLN TYR 0.1 1.4 1181 LYS ILE 0.02−15.06 1181 LYS GLN 0.08 −10.85 1181 LYS GLY 0.09 −2.53 1181 LYS GLU0.37 −7.02 1181 LYS CYS 0.08 −3.3 1181 LYS ASP 0.31 −1.87 1181 LYS SER0.09 −2.18 1181 LYS PRO 0.01 6.45 1181 LYS HIE 0.14 −5.12 1181 LYS ASN0.1 −2.2 1181 LYS HIP −0.09 −5.61 1181 LYS VAL 0.07 −12.85 1181 LYS THR0.08 −6.42 1181 LYS HID 0.13 −7.06 1181 LYS TRP 0.15 −9.89 1181 LYS PHE0.16 −7.87 1181 LYS ALA 0.08 −4.1 1181 LYS MET 0.13 −10.8 1181 LYS LEU0.09 −10.23 1181 LYS ARG −0.1 −19.03 1181 LYS TYR 0.16 −5.84 1182 GLUILE −0.72 3.6 1182 GLU GLN −0.27 3.96 1182 GLU GLY −0.3 22.22 1182 GLUCYS −0.39 13.55 1182 GLU ASP 0.09 10.82 1182 GLU SER −0.35 15.86 1182GLU LYS −0.15 23.9 1182 GLU PRO −0.36 22.59 1182 GLU HIE −0.28 6.2 1182GLU ASN −0.29 10.38 1182 GLU HIP −0.65 15.96 1182 GLU VAL −0.19 7.021182 GLU THR −0.32 11.57 1182 GLU HID −0.39 3.49 1182 GLU TRP −0.3814.07 1182 GLU PHE −0.52 19.79 1182 GLU ALA −0.29 15.93 1182 GLU MET−0.35 2.67 1182 GLU LEU 0.92 4.01 1182 GLU ARG 5.98 5.91 1182 GLU TYR−0.56 17.65 1183 ILE GLN −0.04 11.29 1183 ILE GLY −0.09 19.38 1183 ILEGLU 0.64 15.44 1183 ILE CYS 0.08 14.46 1183 ILE ASP 1.22 23.01 1183 ILESER 0.01 12.94 1183 ILE LYS −0.19 17.23 1183 ILE PRO −0.17 51.45 1183ILE HIE 0.36 12.84 1183 ILE ASN 0.36 13.97 1183 ILE HIP −0.4 13.77 1183ILE VAL −0.09 7.44 1183 ILE THR −0.03 11.04 1183 ILE HID −0.06 11.781183 ILE TRP 0.21 5.41 1183 ILE PHE 0.01 9.39 1183 ILE ALA −0.13 17.251183 ILE MET 0 3.39 1183 ILE LEU −0.04 7.9 1183 ILE ARG −0.41 4.75 1183ILE TYR 0.04 9.85 1184 ASP ILE −0.23 −13 1184 ASP GLN 0.07 −13.27 1184ASP GLY −0.21 −2.69 1184 ASP GLU −0.11 −5.91 1184 ASP CYS −0.27 −6.291184 ASP SER −0.25 −9.91 1184 ASP LYS −0.31 −7.83 1184 ASP PRO −0.2551.91 1184 ASP HIE −0.28 −9.07 1184 ASP ASN −0.26 −6.04 1184 ASP HIP−0.46 −16.92 1184 ASP VAL −0.26 −9.94 1184 ASP THR −0.29 −9.43 1184 ASPHID −0.67 −7.32 1184 ASP TRP −3.46 −4.49 1184 ASP PHE −1.08 −2.24 1184ASP ALA −0.25 −5.83 1184 ASP MET −2.04 −14.02 1184 ASP LEU −0.27 −13.91184 ASP ARG −0.35 −20.06 1184 ASP TYR −0.28 −4.13 1185 ARG ILE 0.256.51 1185 ARG GLN 0.25 7.37 1185 ARG GLY 0.2 18.3 1185 ARG GLU 0.5111.47 1185 ARG CYS 0.2 16.6 1185 ARG ASP 0.57 23.42 1185 ARG SER 0.1114.58 1185 ARG LYS 0.01 12.75 1185 ARG PRO 0.27 89.61 1185 ARG HIE 0.311.33 1185 ARG ASN 0.39 20.19 1185 ARG HIP 0 3.61 1185 ARG VAL 0.2413.19 1185 ARG THR 0.08 12.44 1185 ARG HID 0.22 13.17 1185 ARG TRP 0.5110.73 1185 ARG PHE 0.41 10.73 1185 ARG ALA 0.2 15.96 1185 ARG MET 0.234.64 1185 ARG LEU 0.38 6.49 1185 ARG TYR 0.34 9.47 1186 LEU ILE 0.1120.73 1186 LEU GLN 0.08 15.32 1186 LEU GLY −0.21 31.18 1186 LEU GLU 1.4321.45 1186 LEU CYS −0.13 21.6 1186 LEU ASP 1.14 29.6 1186 LEU SER −0.1822.98 1186 LEU LYS −1.23 35.81 1186 LEU PRO −0.08 70.68 1186 LEU HIE 0.115.43 1186 LEU ASN 0.21 21.51 1186 LEU HIP −0.94 11.73 1186 LEU VAL−0.17 18.2 1186 LEU THR −0.21 17.91 1186 LEU HID 0.48 15.76 1186 LEU TRP0.53 68.2 1186 LEU PHE 0.27 13.47 1186 LEU ALA −0.2 23.51 1186 LEU MET−0.32 1.54 1186 LEU ARG −3.87 16.81 1186 LEU TYR 0.86 24.32 1187 ASN ILE−0.15 −4.61 1187 ASN GLN 0.41 −6.76 1187 ASN GLY 0.03 4.78 1187 ASN GLU0.22 −3.98 1187 ASN CYS 0 −0.39 1187 ASN ASP 0.39 3.5 1187 ASN SER −0.05−0.44 1187 ASN LYS 1 4.91 1187 ASN PRO −0.03 39.08 1187 ASN HIE 0.14−5.31 1187 ASN HIP 0.02 −5.3 1187 ASN VAL −0.1 −1.26 1187 ASN THR −0.14−5.41 1187 ASN HID 0 −2.38 1187 ASN TRP 0.11 −2.94 1187 ASN PHE 0.01−12.18 1187 ASN ALA −0.02 0.27 1187 ASN MET −0.01 −8.9 1187 ASN LEU−0.03 −10.2 1187 ASN ARG 4.71 −6.84 1187 ASN TYR −0.1 −12.12 1188 GLUILE −0.05 2.46 1188 GLU GLN −0.1 −1.94 1188 GLU GLY −0.06 7.98 1188 GLUCYS −0.12 3.57 1188 GLU ASP 0.11 11.19 1188 GLU SER −0.11 8.18 1188 GLULYS −0.44 7.9 1188 GLU PRO −0.07 57.44 1188 GLU HIE −0.12 3.3 1188 GLUASN −0.08 5.95 1188 GLU HIP −0.18 2.89 1188 GLU VAL −0.05 3.56 1188 GLUTHR −0.12 3.54 1188 GLU HID −0.1 2.4 1188 GLU TRP −1.23 0.06 1188 GLUPHE −0.1 1.87 1188 GLU ALA −0.09 4.32 1188 GLU MET −0.12 −3.78 1188 GLULEU −0.12 −1.07 1188 GLU ARG −0.18 −8.12 1188 GLU TYR −0.09 2.69 1189VAL ILE −0.01 −8.72 1189 VAL GLN 0.22 −2.52 1189 VAL GLY −0.22 16.731189 VAL GLU 0.57 4.13 1189 VAL CYS −0.07 7.75 1189 VAL ASP 0.51 12.231189 VAL SER −0.36 8.08 1189 VAL LYS −0.48 13.8 1189 VAL PRO −0.04 56.51189 VAL HIE −0.1 5.02 1189 VAL ASN −0.42 8.63 1189 VAL HIP −0.81 0.811189 VAL THR −0.31 2.98 1189 VAL HID −0.02 4.74 1189 VAL TRP −0.05 9.141189 VAL PHE −0.06 6.41 1189 VAL ALA −0.23 7.78 1189 VAL MET −0.09 −1.991189 VAL LEU −0.08 −9.57 1189 VAL ARG 0.9 −0.93 1189 VAL TYR 0.45 101.851190 ALA ILE 0.04 33.19 1190 ALA GLN 3.52 −1.08 1190 ALA GLY 0.03 5.561190 ALA GLU 9.94 −1.96 1190 ALA CYS −0.27 −0.22 1190 ALA ASP 0.57 7.21190 ALA SER −0.3 −0.46 1190 ALA LYS −1.19 11.56 1190 ALA PRO −0.34120.3 1190 ALA HIE 0.21 4.91 1190 ALA ASN −0.12 5.11 1190 ALA HIP −0.195.99 1190 ALA VAL −0.16 14.94 1190 ALA THR −0.21 −4.03 1190 ALA HID−0.23 1.1 1190 ALA TRP −0.81 28.65 1190 ALA PHE −0.22 8 1190 ALA MET−0.73 −7.35 1190 ALA LEU −0.28 34.7 1190 ALA ARG −0.32 −7.57 1190 ALATYR −5.65 8.56 1191 LYS ILE 0.31 −8.69 1191 LYS GLN 0.39 −4.44 1191 LYSGLY 0.3 3.1 1191 LYS GLU 0.72 1.18 1191 LYS CYS 0.23 −0.05 1191 LYS ASP0.76 6.95 1191 LYS SER 0.25 −1.62 1191 LYS PRO 0.23 50.85 1191 LYS HIE0.34 −2.08 1191 LYS ASN 0.24 −3.52 1191 LYS HIP −0.01 −11.08 1191 LYSVAL 0.3 −5.68 1191 LYS THR 0.2 −3.01 1191 LYS HID 0.25 −8.45 1191 LYSTRP 0.38 0.18 1191 LYS PHE 0.33 −1.07 1191 LYS ALA 0.27 0.22 1191 LYSMET 0.27 −7.48 1191 LYS LEU 0.31 −6.11 1191 LYS ARG 0.09 −17.9 1191 LYSTYR 0.32 −5.02 1191 LYS ILE 0.31 −8.69 1191 LYS GLN 0.39 −4.44 1191 LYSGLY 0.3 3.1 1191 LYS GLU 0.72 1.18 1191 LYS CYS 0.23 −0.05 1191 LYS ASP0.76 6.95 1191 LYS SER 0.25 −1.62 1191 LYS PRO 0.23 50.85 1191 LYS HIE0.34 −2.08 1191 LYS ASN 0.24 −3.52 1191 LYS HIP −0.01 −11.08 1191 LYSVAL 0.3 −5.68 1191 LYS THR 0.2 −3.01 1191 LYS HID 0.25 −8.45 1191 LYSTRP 0.38 0.18 1191 LYS PHE 0.33 −1.07 1191 LYS ALA 0.27 0.22 1191 LYSMET 0.27 −7.48 1191 LYS LEU 0.31 −6.1 1191 LYS ARG 0.09 −17.9 1191 LYSTYR 0.32 −5.02 1191 LYS ILE 0.31 −8.69 1191 LYS GLN 0.39 −4.44 1191 LYSGLY 0.3 3.1 1191 LYS GLU 0.62 1.15 1191 LYS CYS 0.23 −0.05 1191 LYS ASP0.76 6.95 1191 LYS SER 0.25 −1.62 1191 LYS PRO 0.23 50.85 1191 LYS HIE0.34 −2.08 1191 LYS ASN 0.24 −3.52 1191 LYS HIP −0.01 −11.08 1191 LYSVAL 0.3 −5.67 1191 LYS THR 0.2 −3.01 1191 LYS HID 0.25 −8.46 1191 LYSTRP 0.38 0.18 1191 LYS PHE 0.33 −1.07 1191 LYS ALA 0.27 0.22 1191 LYSMET 0.27 −7.48 1191 LYS LEU 0.31 −6.11 1191 LYS ARG 0.09 −17.9 1191 LYSTYR 0.32 −5.02 1191 LYS ILE 0.31 −8.69 1191 LYS GLN 0.39 −4.44 1191 LYSGLY 0.3 3.1 1191 LYS GLU 0.62 1.14 1191 LYS CYS 0.23 −0.05 1191 LYS ASP0.76 6.95 1191 LYS SER 0.25 −1.62 1191 LYS PRO 0.23 50.85 1191 LYS HIE0.34 −2.08 1191 LYS ASN 0.24 −3.52 1191 LYS HIP −0.01 −11.08 1191 LYSVAL 0.3 −5.68 1191 LYS THR 0.2 −3.01 1191 LYS HID 0.25 −8.45 1191 LYSTRP 0.38 0.18 1191 LYS PHE 0.33 −1.07 1191 LYS ALA 0.27 0.22 1191 LYSMET 0.27 −7.48 1191 LYS LEU 0.31 −6.11 1191 LYS ARG 0.09 −17.9 1191 LYSTYR 0.32 −5.02 1191 LYS ILE 0.31 −8.69 1191 LYS GLN 0.39 −4.44 1191 LYSGLY 0.3 3.1 1191 LYS GLU 0.72 1.18 1191 LYS CYS 0.23 −0.05 1191 LYS ASP0.76 6.95 1191 LYS SER 0.25 −1.62 1191 LYS PRO 0.23 50.85 1191 LYS HIE0.35 −2.08 1191 LYS ASN 0.24 −3.52 1191 LYS HIP 0.1 −11.08 1191 LYS VAL0.3 −5.67 1191 LYS THR 0.21 −3.01 1191 LYS HID 0.25 −8.46 1191 LYS TRP0.38 0.18 1191 LYS PHE 0.33 −1.07 1191 LYS ALA 0.27 0.22 1191 LYS MET0.27 −7.48 1191 LYS LEU 0.31 −6.11 1191 LYS ARG 0.09 −17.9 1191 LYS TYR0.32 −5.02 1191 LYS ILE 0.31 −8.69 1191 LYS GLN 0.39 −4.44 1191 LYS GLY0.3 3.1 1191 LYS GLU 0.72 1.17 1191 LYS CYS 0.23 −0.05 1191 LYS ASP 0.766.95 1191 LYS SER 0.25 −1.62 1191 LYS PRO 0.23 50.85 1191 LYS HIE 0.34−2.08 1191 LYS ASN 0.24 −3.52 1191 LYS HIP 0.1 −11.08 1191 LYS VAL 0.3−5.67 1191 LYS THR 0.21 −3.01 1191 LYS HID 0.25 −8.45 1191 LYS TRP 0.380.18 1191 LYS PHE 0.33 −1.07 1191 LYS ALA 0.27 0.22 1191 LYS MET 0.27−7.48 1191 LYS LEU 0.31 −6.11 1191 LYS ARG 0.09 −17.9 1191 LYS TYR 0.32−5.02 1191 LYS ILE 0.31 −8.69 1191 LYS GLN 0.39 −4.44 1191 LYS GLY 0.33.1 1191 LYS GLU 0.72 1.18 1191 LYS CYS 0.23 −0.05 1191 LYS ASP 0.766.95 1191 LYS SER 0.25 −1.62 1191 LYS PRO 0.23 50.85 1191 LYS HIE 0.35−2.08 1191 LYS ASN 0.24 −3.52 1191 LYS HIP 0.1 −11.08 1191 LYS VAL 0.3−5.68 1191 LYS THR 0.2 −3.01 1191 LYS HID 0.25 −8.45 1191 LYS TRP 0.380.18 1191 LYS PHE 0.33 −1.07 1191 LYS ALA 0.27 0.22 1191 LYS MET 0.27−7.48 1191 LYS LEU 0.31 −6.11 1191 LYS ARG 0.09 −17.9 1191 LYS TYR 0.32−5.02 1192 ASN ILE 0.02 −2.36 1192 ASN GLN 0.04 −2.94 1192 ASN GLY −0.030.4 1192 ASN GLU 0.37 4.71 1192 ASN CYS −0.08 −0.43 1192 ASN ASP 0.7 8.71192 ASN SER −0.01 −0.13 1192 ASN LYS −0.3 −0.07 1192 ASN PRO 0.02 66.121192 ASN HIE −0.02 2.97 1192 ASN HIP −0.35 −7.7 1192 ASN VAL −0.02 −2.521192 ASN THR −0.04 −3.28 1192 ASN HID −0.03 2.08 1192 ASN TRP −0.23 3.271192 ASN PHE −0.01 4.52 1192 ASN ALA −0.03 −2.34 1192 ASN MET 0.02 −2.621192 ASN LEU −0.45 −4.27 1192 ASN ARG 2.58 −14.87 1192 ASN TYR 0.36 4.411192 ASN ILE 0.02 −2.36 1192 ASN GLN 0.04 −2.94 1192 ASN GLY −0.03 0.41192 ASN GLU 0.37 4.71 1192 ASN CYS −0.08 −0.43 1192 ASN ASP 0.7 8.71192 ASN SER −0.01 −0.13 1192 ASN LYS −0.3 −0.07 1192 ASN PRO 0.02 66.121192 ASN HIE −0.02 2.97 1192 ASN HIP −0.35 −7.7 1192 ASN VAL −0.02 −2.521192 ASN THR −0.04 −3.28 1192 ASN HID −0.03 2.09 1192 ASN TRP −0.23 3.271192 ASN PHE −0.01 4.52 1192 ASN ALA −0.03 −2.34 1192 ASN MET 0.02 −2.621192 ASN LEU −0.45 −4.27 1192 ASN ARG 2.58 −14.87 1192 ASN TYR 0.36 4.421192 ASN ILE 0.02 −2.36 1192 ASN GLN 0.04 −2.94 1192 ASN GLY −0.03 0.41192 ASN GLU 0.37 4.71 1192 ASN CYS −0.08 −0.43 1192 ASN ASP 0.7 8.71192 ASN SER −0.01 −0.13 1192 ASN LYS −0.3 −0.07 1192 ASN PRO 0.02 66.121192 ASN HIE −0.02 2.97 1192 ASN HIP −0.35 −7.7 1192 ASN VAL −0.02 −2.521192 ASN THR −0.04 −3.28 1192 ASN HID −0.03 2.1 1192 ASN TRP −0.24 3.261192 ASN PHE −0.01 4.52 1192 ASN ALA −0.03 −2.34 1192 ASN MET 0.02 −2.621192 ASN LEU −0.45 −4.27 1192 ASN ARG 2.58 −14.87 1192 ASN TYR 0.36 4.411192 ASN ILE 0.02 −2.36 1192 ASN GLN 0.04 −2.94 1192 ASN GLY −0.03 0.41192 ASN GLU 0.37 4.71 1192 ASN CYS −0.08 −0.43 1192 ASN ASP 0.7 8.71192 ASN SER −0.01 −0.13 1192 ASN LYS −0.3 −0.07 1192 ASN PRO 0.02 66.121192 ASN HIE −0.02 2.97 1192 ASN HIP −0.35 −7.7 1192 ASN VAL −0.02 −2.521192 ASN THR −0.04 −3.28 1192 ASN HID −0.03 2.08 1192 ASN TRP −0.23 3.261192 ASN PHE −0.01 4.52 1192 ASN ALA −0.03 −2.34 1192 ASN MET 0.02 −2.621192 ASN LEU −0.45 −4.27 1192 ASN ARG 2.58 −14.87 1192 ASN TYR 0.36 4.411192 ASN ILE 0.02 −2.36 1192 ASN GLN 0.04 −2.94 1192 ASN GLY −0.03 0.41192 ASN GLU 0.37 4.71 1192 ASN CYS −0.08 −0.43 1192 ASN ASP 0.7 8.71192 ASN SER −0.01 −0.13 1192 ASN LYS −0.3 −0.07 1192 ASN PRO 0.02 66.121192 ASN HIE −0.02 2.97 1192 ASN HIP −0.35 −7.7 1192 ASN VAL −0.02 −2.521192 ASN THR −0.04 −3.28 1192 ASN HID −0.03 2.08 1192 ASN TRP −0.23 3.261192 ASN PHE −0.01 4.52 1192 ASN ALA −0.03 −2.34 1192 ASN MET 0.02 −2.621192 ASN LEU −0.45 −4.27 1192 ASN ARG 2.58 −14.87 1192 ASN TYR 0.36 4.411192 ASN ILE 0.02 −2.36 1192 ASN GLN 0.04 −2.94 1192 ASN GLY −0.03 0.41192 ASN GLU 0.37 4.71 1192 ASN CYS −0.08 −0.43 1192 ASN ASP 0.7 8.71192 ASN SER −0.01 −0.13 1192 ASN LYS −0.3 −0.07 1192 ASN PRO 0.02 66.121192 ASN HIE −0.02 2.97 1192 ASN HIP −0.35 −7.7 1192 ASN VAL −0.02 −2.521192 ASN THR −0.04 −3.28 1192 ASN HID −0.03 2.08 1192 ASN TRP −0.23 3.261192 ASN PHE −0.01 4.52 1192 ASN ALA −0.03 −2.34 1192 ASN MET 0.02 −2.621192 ASN LEU −0.45 −4.27 1192 ASN ARG 2.58 −14.87 1192 ASN TYR 0.36 4.411193 LEU ILE 0.16 13.77 1193 LEU GLN 0.24 15.52 1193 LEU GLY −0.26 28.711193 LEU GLU 1.99 23.61 1193 LEU CYS −0.26 20.25 1193 LEU ASP 1.5 33.531193 LEU SER −0.34 19.68 1193 LEU LYS −2.31 30 1193 LEU PRO 0.08 106.11193 LEU HIE 0.13 17.39 1193 LEU ASN 0.03 22.74 1193 LEU HIP −1.66 13.311193 LEU VAL 0.02 19.32 1193 LEU THR −0.09 19.42 1193 LEU HID 0.44 10.21193 LEU TRP −0.71 61.98 1193 LEU PHE −0.11 22.23 1193 LEU ALA −0.322.87 1193 LEU MET −0.22 −5.85 1193 LEU ARG −2.22 10.71 1193 LEU TYR0.13 27.38 1193 LEU ILE 0.16 13.77 1193 LEU GLN 0.24 15.52 1193 LEU GLY−0.26 28.71 1193 LEU GLU 1.99 23.61 1193 LEU CYS −0.26 20.25 1193 LEUASP 1.5 33.53 1193 LEU SER −0.34 19.68 1193 LEU LYS −2.31 30 1193 LEUPRO 0.08 106.1 1193 LEU HIE 0.13 17.39 1193 LEU ASN 0.03 22.74 1193 LEUHIP −1.66 13.31 1193 LEU VAL 0.02 19.32 1193 LEU THR −0.09 19.42 1193LEU HID 0.44 10.21 1193 LEU TRP −0.71 61.98 1193 LEU PHE −0.11 22.231193 LEU ALA −0.3 22.87 1193 LEU MET −0.22 −5.85 1193 LEU ARG −2.2210.71 1193 LEU TYR 0.13 27.38 1193 LEU ILE 0.16 13.77 1193 LEU GLN 0.2415.52 1193 LEU GLY −0.26 28.71 1193 LEU GLU 1.99 23.61 1193 LEU CYS−0.26 20.25 1193 LEU ASP 1.5 33.53 1193 LEU SER −0.34 19.68 1193 LEU LYS−2.31 30 1193 LEU PRO 0.08 106.1 1193 LEU HIE 0.13 17.39 1193 LEU ASN0.03 22.74 1193 LEU HIP −1.66 13.31 1193 LEU VAL 0.02 19.32 1193 LEU THR−0.09 19.42 1193 LEU HID 0.44 10.21 1193 LEU TRP −0.71 61.98 1193 LEUPHE −0.11 22.23 1193 LEU ALA −0.3 22.87 1193 LEU MET −0.22 −5.85 1193LEU ARG −2.22 10.71 1193 LEU TYR 0.13 27.38 1193 LEU ILE 0.16 13.77 1193LEU GLN 0.24 15.52 1193 LEU GLY −0.26 28.71 1193 LEU GLU 1.99 23.61 1193LEU CYS −0.26 20.25 1193 LEU ASP 1.5 33.53 1193 LEU SER −0.34 19.68 1193LEU LYS −2.31 30 1193 LEU PRO 0.08 106.1 1193 LEU HIE 0.13 17.39 1193LEU ASN 0.03 22.74 1193 LEU HIP −1.66 13.31 1193 LEU VAL 0.02 19.32 1193LEU THR −0.09 19.42 1193 LEU HID 0.44 10.21 1193 LEU TRP −0.71 61.981193 LEU PHE −0.11 22.23 1193 LEU ALA −0.3 22.87 1193 LEU MET −0.22−5.85 1193 LEU ARG −2.22 10.71 1193 LEU TYR 0.13 27.38 1193 LEU ILE 0.1613.77 1193 LEU GLN 0.24 15.52 1193 LhU GLY −0.26 28.71 1193 LEU GLU 1.9923.61 1193 LEU CYS −0.26 20.25 1193 LEU ASP 1.5 33.53 1193 LEU SER −0.3419.68 1193 LEU LYS −2.31 30 1193 LEU PRO 0.08 106.1 1193 LEU HIE 0.1317.39 1193 LEU ASN 0.03 22.74 1193 LEU HIP −1.66 13.31 1193 LEU VAL 0.0219.32 1193 LEU THR −0.09 19.42 1193 LEU HID 0.44 10.2 1193 LEU TRP −0.7161.98 1193 LEU PHE −0.11 22.23 1193 LEU ALA −0.3 22.87 1193 LEU MET−0.22 −5.85 1193 LEU ARG −2.22 10.71 1193 LEU TYR 0.13 27.38 1194 ASNILE −0.1 2.69 1194 ASN GLN −0.07 1.46 1194 ASN GLY −0.1 4.6 1194 ASN GLU0.47 3.35 1194 ASN CYS −0.15 1.55 1194 ASN ASP 0.49 3.82 1194 ASN SER−0.13 0.96 1194 ASN LYS −0.34 4.05 1194 ASN PRO −0.33 81.47 1194 ASN HIE0.1 −1.11 1194 ASN HIP −0.51 −4.03 1194 ASN VAL −0.11 3.91 1194 ASN THR−0.14 0.78 1194 ASN HID −0.03 3.36 1194 ASN TRP −3.34 7.76 1194 ASN PHE−0.04 −4.66 1194 ASN ALA −0.12 1.83 1194 ASN MET −0.03 −3.02 1194 ASNLEU −0.22 −3.38 1194 ASN ARG −0.51 −2.6 1194 ASN TYR 0.12 −3.72 1194 ASNILE −0.1 2.69 1194 ASN GLN −0.07 1.46 1194 ASN GLY −0.1 4.6 1194 ASN GLU0.47 3.35 1194 ASN CYS −0.15 1.55 1194 ASN ASP 0.49 3.82 1194 ASN SER−0.13 0.96 1194 ASN LYS −0.34 4.05 1194 ASN PRO −0.33 81.47 1194 ASN HIE0.1 −1.11 1194 ASN HIP −0.51 −4.03 1194 ASN VAL −0.11 3.91 1194 ASN THR−0.14 0.78 1194 ASN HID −0.03 3.36 1194 ASN TRP −3.34 7.76 1194 ASN PHE−0.04 −4.66 1194 ASN ALA −0.12 1.83 1194 ASN MET −0.03 −3.02 1194 ASNLEU −0.22 −3.38 1194 ASN ARG −0.51 −2.6 1194 ASN TYR 0.12 −3.72 1194 ASNILE −0.1 2.69 1194 ASN GLN −0.07 1.46 1194 ASN GLY −0.1 4.6 1194 ASN GLU0.47 3.35 1194 ASN CYS −0.15 1.55 1194 ASN ASP 0.49 3.82 1194 ASN SER−0.13 0.96 1194 ASN LYS −0.34 4.05 1194 ASN PRO −0.33 81.47 1194 ASN HIE0.1 −1.11 1194 ASN HIP −0.51 −4.03 1194 ASN VAL −0.11 3.91 1194 ASN THR−0.14 0.78 1194 ASN HID −0.03 3.36 1194 ASN TRP −3.34 7.76 1194 ASN PHE−0.04 −4.66 1194 ASN ALA −0.12 1.83 1194 ASN MET −0.03 −3.02 1194 ASNLEU −0.22 −3.38 1194 ASN ARG −0.51 −2.6 1194 ASN TYR 0.12 −3.72 1194 ASNILE −0.1 2.69 1194 ASN GLN −0.07 1.46 1194 ASN GLY −0.1 4.6 1194 ASN GLU0.47 3.35 1194 ASN CYS −0.15 1.55 1194 ASN ASP 0.49 3.82 1194 ASN SER−0.13 0.96 1194 ASN LYS −0.34 4.05 1194 ASN PRO −0.33 81.47 1194 ASN HIE0.1 −1.11 1194 ASN HIP −0.51 −4.03 1194 ASN VAL −0.11 3.91 1194 ASN THR−0.14 0.78 1194 ASN HID −0.03 3.36 1194 ASN TRP −3.34 7.76 1194 ASN PHE−0.04 −4.66 1194 ASN ALA −0.12 1.83 1194 ASN MET −0.03 −3.02 1194 ASNLEU −0.22 −3.38 1194 ASN ARG −0.51 −2.6 1194 ASN TYR 0.12 −3.72 1195 GLUILE −0.38 −0.14 1195 GLU GLN −0.31 2.04 1195 GLU GLY −0.33 10.76 1195GLU CYS −0.37 9.38 1195 GLU ASP 0.09 10.03 1195 GLU SER −0.33 10.85 1195GLU LYS −0.69 9.74 1195 GLU PRO −0.38 26.49 1195 GLU HIE −0.3 3.75 1195GLU ASN −0.35 9.28 1195 GLU HIP −0.68 0.94 1195 GLU VAL −0.35 2.77 1195GLU THR −0.45 10.08 1195 GLU HID −0.3 5.64 1195 GLU TRP −0.56 2.37 1195GLU PHE −0.8 5.44 1195 GLU ALA −0.33 8.83 1195 GLU MET −0.35 2.02 1195GLU LEU −0.36 0.82 1195 GLU ARG −0.71 −3.71 1195 GLU TYR −0.35 2.85 1195GLU ILE −0.38 −0.14 1195 GLU GLN −0.31 2.04 1195 GLU GLY −0.33 10.761195 GLU CYS −0.37 9.38 1195 GLU ASP 0.09 10.03 1195 GLU SER −0.33 10.851195 GLU LYS −0.69 9.74 1195 GLU PRO −0.38 26.49 1195 GLU HIE −0.3 3.751195 GLU ASN −0.35 9.28 1195 GLU HIP −0.68 0.94 1195 GLU VAL −0.35 2.771195 GLU THR −0.45 10.08 1195 GLU HID −0.3 5.64 1195 GLU TRP −0.56 2.371195 GLU PHE −0.8 5.44 1195 GLU ALA −0.33 8.83 1195 GLU MET −0.35 2.021195 GLU LEU −0.36 0.82 1195 GLU ARG −0.71 −3.71 1195 GLU TYR −0.35 2.851195 GLU ILE −0.38 −0.14 1195 GLU GLN −0.31 2.04 1195 GLU GLY −0.3310.76 1195 GLU CYS −0.37 9.38 1195 GLU ASP 0.09 10.03 1195 GLU SER −0.3310.85 1195 GLU LYS −0.69 9.74 1195 GLU PRO −0.38 26.49 1195 GLU HIE −0.33.75 1195 GLU ASN −0.35 9.28 1195 GLU HIP −0.68 0.94 1195 GLU VAL −0.352.77 1195 GLU THR −0.45 10.08 1195 GLU HID −0.3 5.64 1195 GLU TRP −0.562.37 1195 GLU PHE −0.8 5.44 1195 GLU ALA −0.33 8.83 1195 GLU MET −0.352.02 1195 GLU LEU −0.36 0.82 1195 GLU ARG −0.71 −3.71 1195 GLU TYR −0.352.85 1195 GLU ILE −0.38 −0.14 1195 GLU GLN −0.31 2.04 1195 GLU GLY −0.3310.76 1195 GLU CYS −0.37 9.38 1195 GLU ASP 0.09 10.03 1195 GLU SER −0.3310.85 1195 GLU LYS −0.69 9.74 1195 GLU PRO −0.38 26.49 1195 GLU HIE −0.33.75 1195 GLU ASN −0.35 9.28 1195 GLU HIP −0.68 0.94 1195 GLU VAL −0.352.77 1195 GLU THR −0.45 10.08 1195 GLU HID −0.3 5.64 1195 GLU TRP −0.562.37 1195 GLU PHE −0.8 5.44 1195 GLU ALA −0.33 8.83 1195 GLU MET −0.352.02 1195 GLU LEU −0.36 0.82 1195 GLU ARG −0.71 −3.71 1195 GLU TYR −0.352.85 1196 SER ILE 0.36 38.8 1196 SER GLN 0.02 36.11 1196 SER GLY −0.1414 1196 SER GLU 1.96 42.29 1196 SER CYS 0.02 6.02 1196 SER ASP 2.1841.52 1196 SER LYS −0.28 47.76 1196 SER PRO 0.04 44.44 1196 SER HIE−1.49 30.01 1196 SER ASN −0.37 21.18 1196 SER HIP −0.35 22.79 1196 SERVAL −0.21 16.49 1196 SER THR −0.41 5.74 1196 SER HID −1.16 31.04 1196SER TRP 0.11 1168.4 1196 SER PHE −0.08 52.68 1196 SER ALA −0.13 2.811196 SER MET −2.23 29.3 1196 SER LEU 0.02 83.13 1196 SER ARG −0.69 30.721196 SER TYR 0.01 1248.22 1196 SER ILE 0.36 38.8 1196 SER GLN 0.02 36.111196 SER GLY −0.14 14 1196 SER GLU 1.96 42.29 1196 SER CYS 0.02 6.021196 SER ASP 2.18 41.52 1196 SER LYS −0.28 47.76 1196 SER PRO 0.04 44.441196 SER HIE −1.63 29.97 1196 SER ASN −0.37 21.18 1196 SER HIP −0.3522.79 1196 SER VAL −0.21 16.49 1196 SER THR −0.41 5.74 1196 SER HID 0.04206.17 1196 SER TRP 0.11 1168.4 1196 SER PHE −0.08 52.68 1196 SER ALA−0.13 2.81 1196 SER MET −2.23 29.3 1196 SER LEU 0.02 83.13 1196 SER ARG−0.69 30.72 1196 SER TYR 0.01 1248.22 1196 SER ILE 0.36 38.8 1196 SERGLN 0.02 36.11 1196 SER GLY −0.14 14 1196 SER GLU 1.96 42.29 1196 SERCYS 0.02 6.02 1196 SER ASP 2.18 41.52 1196 SER LYS −0.28 47.76 1196 SERPRO 0.04 44.44 1196 SER HIE −1.61 30.02 1196 SER ASN −0.37 21.18 1196SER HIP −0.35 22.79 1196 SER VAL −0.21 16.49 1196 SER THR −0.41 5.741196 SER HID 0.04 206.17 1196 SER TRP 0.11 1168.4 1196 SER PHE −0.0852.68 1196 SER ALA −0.13 2.81 1196 SER MET −2.23 29.3 1196 SER LEU 0.0283.13 1196 SER ARG −0.69 30.72 1196 SER TYR 0.01 1248.22 1197 LEU ILE−0.1 7.67 1197 LEU GLN 0.42 10.97 1197 LEU GLY −0.2 17.43 1197 LEU GLU1.31 19.23 1197 LEU CYS −0.38 12.64 1197 LEU ASP 1.07 25.71 1197 LEU SER−0.31 16.02 1197 LEU LYS −0.62 9.25 1197 LEU PRO −0.35 28.3 1197 LEU HIE−0.08 9.93 1197 LEU ASN −0.09 13.16 1197 LEU HIP −0.89 −0.31 1197 LEUVAL −0.13 7.45 1197 LEU THR −0.23 9.73 1197 LEU HID −0.16 9.49 1197 LEUTRP 0.49 7.54 1197 LEU PHE 0.32 6.8 1197 LEU ALA −0.2 14.75 1197 LEU MET0.31 1.57 1197 LEU ARG −0.93 −7.32 1197 LEU TYR 0.24 −0.84 1197 LEU ILE−0.1 7.67 1197 LEU GLN 0.42 10.97 1197 LEU GLY −0.2 17.43 1197 LEU GLU1.31 19.23 1197 LEU CYS −0.38 12.64 1197 LEU ASP 1.07 25.71 1197 LEU SER−0.31 16.02 1197 LEU LYS −0.62 9.25 1197 LEU PRO −0.35 28.3 1197 LEU HIE−0.08 9.93 1197 LEU ASN −0.09 13.16 1197 LEU HIP −0.89 −0.31 1197 LEUVAL −0.13 7.45 1197 LEU THR −0.23 9.73 1197 LEU HID −0.16 9.49 1197 LEUTRP 0.49 7.54 1197 LEU PHE 0.32 6.8 1197 LEU ALA −0.2 14.75 1197 LEU MET0.31 1.57 1197 LEU ARG −0.93 −7.32 1197 LEU TYR 0.24 −0.84 1197 LEU ILE−0.1 7.67 1197 LEU GLN 0.42 10.97 1197 LEU GLY −0.2 17.43 1197 LEU GLU1.31 19.23 1197 LEU CYS −0.38 12.64 1197 LEU ASP 1.07 25.71 1197 LEU SER−0.31 16.02 1197 LEU LYS −0.62 9.25 1197 LEU PRO −0.35 28.3 1197 LEU HIE−0.08 9.93 1197 LEU ASN −0.09 13.16 1197 LEU HIP −0.89 −0.31 1197 LEUVAL −0.13 7.45 1197 LEU THR −0.23 9.73 1197 LEU HID −0.16 9.49 1197 LEUTRP 0.49 7.54 1197 LEU PHE 0.32 6.8 1197 LEU ALA −0.2 14.75 1197 LEU MET0.31 1.57 1197 LEU ARG −0.93 −7.32 1197 LEU TYR 0.24 −0.84 1198 ILE GLN0.47 12.38 1198 ILE GLY −0.28 30.62 1198 ILE GLU 1.41 20.73 1198 ILE CYS−0.37 19.52 1198 ILE ASP 1.45 36.51 1198 ILE SER −0.32 23.06 1198 ILELYS −2.14 32.52 1198 ILE PRO −0.25 92.49 1198 ILE HIE −0.5 23.61 1198ILE ASN −0.16 25.31 1198 ILE HIP −1.55 28.43 1198 ILE VAL −0.13 8.891198 ILE THR −0.22 14.76 1198 ILE HID 0.24 25.61 1198 ILE TRP −0.6281.97 1198 ILE PHE 0.33 25.87 1198 ILE ALA −0.25 22.81 1198 ILE MET−0.13 −1.72 1198 ILE LEU −0.21 5.28 1198 ILE ARG −2.14 19.83 1198 ILETYR −0.15 85.23 1198 ILE GLN 0.47 12.38 1198 ILE GLY −0.28 30.62 1198ILE GLU 1.41 20.73 1198 ILE CYS −0.37 19.52 1198 ILE ASP 1.45 36.51 1198ILE SER −0.32 23.06 1198 ILE LYS −2.14 32.52 1198 ILE PRO −0.25 92.491198 ILE HIE −0.5 23.61 1198 ILE ASN −0.16 25.31 1198 ILE HIP −1.5528.43 1198 ILE VAL −0.13 8.89 1198 ILE THR −0.22 14.76 1198 ILE HID 0.2425.61 1198 ILE TRP −0.62 81.97 1198 ILE PHE 0.33 25.87 1198 ILE ALA−0.25 22.81 1198 ILL MET −0.13 −1.72 1198 ILE LEU −0.21 5.28 1198 ILEARG −2.14 19.83 1198 ILE TYR −0.15 85.23 1198 ILE GLN 0.47 12.38 1198ILE GLY −0.28 30.62 1198 ILE GLU 1.41 20.73 1198 ILE CYS −0.37 19.521198 ILE ASP 1.45 36.51 1198 ILE SER −0.32 23.06 1198 ILE LYS −2.1432.52 1198 ILE PRO −0.25 92.49 1198 ILE HIE −0.5 23.61 1198 ILE ASN−0.16 25.31 1198 ILE HIP −1.55 28.43 1198 ILE VAL −0.13 8.89 1198 ILETHR −0.22 14.76 1198 ILE HID 0.24 25.61 1198 ILE TRP −0.62 81.97 1198ILE PHE 0.33 25.87 1198 ILE ALA −0.25 22.81 1198 ILE MET −0.13 −1.721198 ILE LEU −0.21 5.28 1198 ILE ARG −2.14 19.83 1198 ILE TYR −0.1585.23 1199 ASP ILE −0.46 −8.5 1199 ASP GLN 0.11 −6.32 1199 ASP GLY −0.5−1.39 1199 ASP GLU 0.85 −3.56 1199 ASP CYS −0.54 −1.39 1199 ASP SER−0.49 −2.19 1199 ASP LYS −0.76 −3.86 1199 ASP PRO −0.64 4.86 1199 ASPHIE −0.27 −8.66 1199 ASP ASN −0.5 −1.25 1199 ASP HIP −0.09 −12 1199 ASPVAL −0.48 −4.63 1199 ASP THR −0.49 −5.15 1199 ASP HID −0.32 −3.22 1199ASP TRP −0.23 −4.97 1199 ASP PHE −0.2 −8.4 1199 ASP ALA −0.51 −2.63 1199ASP MET −3.47 −7.64 1199 ASP LEU −0.43 −10.26 1199 ASP ARG −0.87 −15.571199 ASP TYR −8.73 −1.87 1199 ASP ILE −0.46 −8.5 1199 ASP GLN 0.11 −6.321199 ASP GLY −0.5 −1.39 1199 ASP GLU 0.85 −3.56 1199 ASP CYS −0.54 −1.391199 ASP SER −0.49 −2.19 1199 ASP LYS −0.76 −3.86 1199 ASP PRO −0.644.86 1199 ASP HIE −0.27 −8.66 1199 ASP ASN −0.5 −1.25 1199 ASP HIP −0.09−12 1199 ASP VAL −0.48 −4.63 1199 ASP THR −0.49 −5.15 1199 ASP HID −0.32−3.22 1199 ASP TRP −0.23 −5.09 1199 ASP PHE −0.2 −8.4 1199 ASP ALA −0.51−2.63 1199 ASP MET −3.47 −7.64 1199 ASP LEU −0.43 −10.26 1199 ASP ARG−0.89 −14.04 1199 ASP TYR −24.62 −1.17 1199 ASP ILE −0.46 −8.5 1199 ASPGLN 0.11 −6.32 1199 ASP GLY −0.5 −1.39 1199 ASP GLU 0.85 −3.56 1199 ASPCYS −0.54 −1.39 1199 ASP SER −0.49 −2.19 1199 ASP LYS −0.76 −3.86 1199ASP PRO −0.64 4.86 1199 ASP HIE −0.27 −8.66 1199 ASP ASN −0.5 −1.25 1199ASP HIP −0.09 −12 1199 ASP VAL −0.48 −4.63 1199 ASP THR −0.49 −5.15 1199ASP HID −0.32 −3.22 1199 ASP TRP −0.23 −4.99 1199 ASP PHE −0.2 −8.4 1199ASP ALA −0.51 −2.63 1199 ASP MET −3.47 −7.64 1199 ASP LEU −0.43 −10.261199 ASP ARG −0.88 −14.27 1199 ASP TYR −18.07 0.23 1200 LEU ILE −0.053.56 1200 LEU GLN −0.04 12.76 1200 LEU GLY −0.12 18.08 1200 LEU GLU 0.7812.64 1200 LEU CYS −0.18 15.48 1200 LEU ASP 0.62 19.81 1200 LEU SER−0.15 17.05 1200 LEU LYS −0.74 25.5 1200 LEU PRO −0.21 12.44 1200 LEUHIE 0.07 13.43 1200 LEU ASN −0.07 17.12 1200 LEU HIP −0.68 15.43 1200LEU VAL −0.1 12.86 1200 LEU THR −0.02 16.64 1200 LEU HID −0.17 11.171200 LEU TRP −0.14 11.88 1200 LEU PHE −0.12 11.14 1200 LEU ALA −0.1314.59 1200 LEU MET 0 1.63 1200 LEU ARG −0.62 16.55 1200 LEU TYR −0.1312.36 1200 LEU ILE −0.05 3.56 1200 LEU GLN −0.04 12.76 1200 LEU GLY−0.12 18.08 1200 LEU GLU 0.78 12.64 1200 LEU CYS −0.18 15.48 1200 LEUASP 0.62 19.81 1200 LEU SER −0.15 17.05 1200 LEU LYS −0.74 25.5 1200 LEUPRO −0.21 12.44 1200 LEU HIE 0.07 13.43 1200 LEU ASN −0.07 17.12 1200LEU HIP −0.68 15.43 1200 LEU VAL −0.1 12.86 1200 LEU THR −0.02 16.641200 LEU HID −0.17 11.17 1200 LEU TRP −0.14 11.88 1200 LEU PHE −0.1211.14 1200 LEU ALA −0.13 14.59 1200 LEU MET 0 1.63 1200 LEU ARG −0.6216.55 1200 LEU TYR −0.13 12.36 1200 LEU ILE −0.05 3.56 1200 LEU GLN−0.04 12.76 1200 LEU GLY −0.12 18.08 1200 LEU GLU 0.78 12.64 1200 LEUCYS −0.18 15.48 1200 LEU ASP 0.62 19.81 1200 LEU SER −0.15 17.05 1200LEU LYS −0.74 25.5 1200 LEU PRO −0.21 12.44 1200 LEU HIE 0.07 13.43 1200LEU ASN −0.07 17.12 1200 LEU HIP −0.68 15.43 1200 LEU VAL −0.1 12.861200 LEU THR −0.02 16.64 1200 LEU HID −0.17 11.17 1200 LEU TRP −0.1411.88 1200 LEU PHE −0.12 11.14 1200 LEU ALA −0.13 14.59 1200 LEU MET 01.63 1200 LEU ARG −0.62 16.55 1200 LEU TYR −0.13 12.36 1201 GLN ILE 0.061.13 1201 GLN GLY 0.01 9.26 1201 GLN GLU 0.5 7.74 1201 GLN CYS −0.04 7.91201 GLN ASP 0.57 9.56 1201 GLN SER −0.02 9.76 1201 GLN LYS 0.65 4.591201 GLN PRO −0.02 10.24 1201 GLN HIE 0.03 4.52 1201 GLN ASN −0.02 7.011201 GLN HIP −0.37 −1 1201 GLN VAL 0.05 3.21 1201 GLN THR 0.07 8.5 1201GLN HID 0.02 6.2 1201 GLN TRP −0.05 7.08 1201 GLN PHE 0.17 3.93 1201 GLNALA 0 4.8 1201 GLN MET −0.03 −6.12 1201 GLN LEU 0.08 0.44 1201 GLN ARG−0.31 −2.41 1201 GLN TYR 0.2 4.36 1201 GLN ILE 0.06 1.13 1201 GLN GLY0.01 9.26 1201 GLN GLU 0.5 7.74 1201 GLN CYS −0.04 7.9 1201 GLN ASP 0.579.45 1201 GLN SER −0.02 9.76 1201 GLN LYS 0.65 4.59 1201 GLN PRO −0.0210.24 1201 GLN HIE 0.03 4.52 1201 GLN ASN −0.02 7.01 1201 GLN HIP −0.37−1 1201 GLN VAL 0.05 3.21 1201 GLN THR 0.07 8.5 1201 GLN HID 0.02 6.21201 GLN TRP −0.05 7.08 1201 GLN PHE 0.17 3.93 1201 GLN ALA 0 4.8 1201GLN MET −0.03 −6.12 1201 GLN LEU 0.08 0.44 1201 GLN ARG −0.31 −2.41 1201GLN TYR 0.2 4.36 1201 GLN ILE 0.06 1.13 1201 GLN GLY 0.01 9.26 1201 GLNGLU 0.5 7.74 1201 GLN CYS −0.04 7.9 1201 GLN ASP 0.57 9.33 1201 GLN SER−0.02 9.76 1201 GLN LYS 0.65 4.59 1201 GLN PRO −0.02 10.24 1201 GLN HIE0.03 4.52 1201 GLN ASN −0.02 7.01 1201 GLN HIP −0.37 −1 1201 GLN VAL0.05 3.21 1201 GLN THR 0.07 8.5 1201 GLN HID 0.02 6.2 1201 GLN TRP −0.057.08 1201 GLN PHE 0.17 3.93 1201 GLN ALA 0 4.8 1201 GLN MET −0.03 −6.121201 GLN LEU 0.08 0.44 1201 GLN ARG −0.33 −2.39 1201 GLN TYR 0.2 4.361202 GLU ILE −0.45 41.43 1202 GLU GLN −0.42 −15.68 1202 GLU GLY −0.4418.98 1202 GLU CYS −0.48 25.13 1202 GLU ASP 0 −10.67 1202 GLU SER −0.4324.92 1202 GLU LYS −0.4 21.88 1202 GLU PRO −0.5 86.02 1202 GLU HIE −0.4112.12 1202 GLU ASN −0.44 −14.97 1202 GLU HIP −0.84 18.29 1202 GLU VAL−0.45 35.37 1202 GLU THR −0.42 24.36 1202 GLU HID −0.45 19.72 1202 GLUTRP −0.42 8.84 1202 GLU PHE −0.45 28.47 1202 GLU ALA −0.43 24.3 1202 GLUMET −0.42 17.22 1202 GLU LEU −0.82 32.05 1202 GLU ARG −1.01 −7.58 1202GLU TYR −0.43 20.74 1202 GLU ILE −0.45 41.43 1202 GLU GLN −0.42 −15.681202 GLU GLY −0.44 18.98 1202 GLU CYS −0.48 25.13 1202 GLU ASP 0 −10.671202 GLU SER −0.43 24.92 1202 GLU LYS −0.4 21.88 1202 GLU PRO −0.5 86.021202 GLU HIE −0.41 12.12 1202 GLU ASN −0.44 −14.97 1202 GLU HIP −0.8418.29 1202 GLU VAL −0.45 35.37 1202 GLU THR −0.42 24.36 1202 GLU HID−0.45 19.72 1202 GLU TRP −0.41 8.74 1202 GLU PHE −0.45 28.47 1202 GLUALA −0.43 24.3 1202 GLU MET −0.42 17.22 1202 GLU LEU −0.82 32.05 1202GLU ARG −1.01 −7.58 1202 GLU TYR −0.43 20.74 1202 GLU ILE −0.45 41.431202 GLU GLN −0.42 −15.68 1202 GLU GLY −0.44 18.98 1202 GLU CYS −0.4825.13 1202 GLU ASP 0 −10.67 1202 GLU SER −0.43 24.92 1202 GLU LYS −0.421.88 1202 GLU PRO −0.5 86.02 1202 GLU HIE −0.41 12.12 1202 GLU ASN−0.44 −14.97 1202 GLU HIP −0.84 18.29 1202 GLU VAL −0.45 35.37 1202 GLUTHR −0.42 24.36 1202 GLU HID −0.45 19.72 1202 GLU TRP −0.42 8.37 1202GLU PHE −0.45 28.48 1202 GLU ALA −0.43 24.3 1202 GLU MET −0.42 17.221202 GLU LEU −0.82 32.05 1202 GLU ARG −1.01 −7.58 1202 GLU TYR −0.4320.74

Example 2 Energy Maturation Studies

The HR2 structure was further engineered by introduction of severalmutations based on the results of the initial residues scanningmutations as described in Example 1. (Schrodinger Suite 2020, NY, USA)The calculations included both stability and affinity options. The sidechains were mutated followed by backbone minimization. Affinitymaturations upon amino acids mutations was performed using Monte Carlooptimizations of maximal 2000 steps and maximal 6 deviations from theinput structure. Based on the results of Δ affinity and Δ stability fromthe single amino acids mutations, 63 mutations were used in energymaturation studies (Table 2).

TABLE 2 The 63 Mutations Used for Energy Maturation Studies Mutation #WT Residue # MUT 1 VAL 1164 HIS 2 VAL 1164 LYS 3 ASP 1165 CYS 4 ASP 1165ILE 5 ASP 1165 SER 6 ASP 1165 GLN 7 ASP 1165 LYS 8 ASP 1165 GLY 9 ASP1165 LEU 10 ASP 1165 ARG 11 ASP 1165 VAL 12 ASP 1165 MET 13 GLY 1167 ARG14 ASP 1168 HIS 15 ASP 1168 MET 16 ASP 1168 ASN 17 ASP 1168 GLN 18 ASP1168 ARG 19 SER 1170 HIS 20 SER 1170 ARG 21 ASN 1173 HIS 77 ASN 1173 LYS23 ASN 1173 ARG 24 SER 1175 MET 25 SER 1175 ILE 26 SER 1175 ARG 27 ASN1178 MET 28 ASN 1178 GLN 29 ASN 1178 ARG 30 ARG 1184 CYS 31 ARG 1184 HIS32 ARG 1184 ILE 33 ARG 1184 VAL 34 ARG 1184 LYS 35 ARG 1184 THR 36 ARG1184 PHE 37 ARG 1184 ALA 38 ARG 1184 MET 39 ARG 1184 HIS 40 ARG 1184 ARG41 ARG 1184 TRP 42 ARG 1184 ASN 43 ARG 1184 LEU 44 ALA 1190 MET 45 ALA1190 ARG 46 ASN 1192 HIS 47 ASN 1192 LEU 48 LEU 1193 MET 49 ASN 1194 HIS50 ASN 1194 LEU 51 GLU 1195 ARG 52 LEU 1197 ARG 53 ASP 1199 ILE 54 ASP1199 SER 55 ASP 1199 VAL 56 ASP 1199 LYS 57 ASP 1199 MET 58 ASP 1199 LEU59 ASP 1199 ARG 60 ASP 1199 TYR 61 ASP 1199 HIS 62 GLU 1202 ASN 63 GLU1202 ARG

The top single amino acids mutants with the highest changes in affinityand favorable stability were combined using a Monte Carlo approach.About 320 mutant HR2 proteins were generated containing a combination ofup to 6 mutant residues, compared with the wild type (Table 3). Fromthis list, one peptide was selected with the highest affinity scores.The peptide no. 317 (termed #121) was retrieved with Δ affinity score−13.51 and a Δ stability equaling −24.88. The second peptide was no. 129(termed #122) showed Δ affinity score −3.93 and A Stability equals−66.91. Therefore, #121 (SEQ ID NO: 2) has higher affinity than #122 butlower stability. Peptide #121 (SEQ ID NO: 2) and peptide #122 (SEQ IDNO: 3), having 5 and 6 mutations, had been selected after energymaturation step. Peptide #125 (SEQ ID NO: 5) comprises 11 amino acidmutations which were inserted into their sites by combining the topaffinity changes after initial single amino acid mutations. Thesequences of peptides #120 (SEQ ID NO: 1), #121 (SEQ ID NO: 2), #122(SEQ ID NO: 3), and #125 (SEQ ID No: 5) are presented in Table 4, withthe mutated residues underlined.

TABLE 3 The Results of Energy Maturation by Monte Carlo Methods forCombining Several Mutations in HR2 Structure MUT # Mutations Δ AffinityΔ Stability 1 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG),−3.15 −90.5116 A: 1178(ASN−>ARG), A: 1184(ASP−>ARG), A: 1202(GLU−>ASN) 2A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −3.20835−86.7075 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP), A: 1202(GLU−>ASN) 3 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.86123 −86.3462A: 1178(ASN−>ARG), A: 1184(ASP−>ARG), A: 1202(GLU−>ASN) 4 A:1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.26125 −85.0375A: 1178(ASN−>ARG), A: 1184(ASP−>ARG), A: 1202(GLU−>ASN) 5 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −3.14849 −84.3989A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), A: 1202(GLU−>ASN) 6 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −3.13824 −84.3851A: 1178(ASN−>ARG), A: 1184(ASP−>MET), A: 1202(GLU−>ASN) 7 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −3.11404 −83.5476A: 1178(ASN−>ARG), A: 1184(ASP−>ILE), A: 1202(GLU−>ASN) 8 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.92024 −82.5475A: 1178(ASN−>ARG), A: 1184(ASP−>HIP), A: 1202(GLU−>ASN) 9 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ILE), −2.63282 −82.2024A: 1178(ASN−>ARG), A: 1184(ASP−>ARG), A: 1202(GLU−>ASN) 10 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.82403 −81.444A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), A: 1202(GLU−>ASN) 11 A:1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −1.97265 −80.712A: 1178(ASN−>ARG), A: 1184(ASP−>ARG), A: 1202(GLU−>ASN) 12 A:1164(VAL−>LYS), A: 1175(SER−>ARG), A: 1178(ASN−>ARG), −2.41396 −80.6946A: 1184(ASP−>ARG), A: 1202(GLU−>ASN) 13 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −3.13885 −80.4482 A: 1178(ASN−>ARG),A: 1184(ASP−>VAL), A: 1202(GLU−>ASN) 14 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>MET), −2.87162 −80.2281 A: 1178(ASN−>ARG),A: 1184(ASP−>MET), A: 1202(GLU−>ASN) 15 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −3.16949 −79.9326 A: 1178(ASN−>ARG),A: 1184(ASP−>THR), A: 1202(GLU−>ASN) 16 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −2.9837 −79.8882 A: 1178(ASN−>ARG),A: 1184(ASP−>ARG), A: 1190(ALA−>MET) 17 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −3.16017 −79.5818 A: 1178(ASN−>ARG),A: 1184(ASP−>HIE), A: 1202(GLU−>ASN) 18 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −3.20243 −79.5381 A: 1178(ASN−>ARG),A: 1184(ASP−>LYS), A: 1202(GLU−>ASN) 19 A: 1164(VAL−>LYS), A:1173(ASP−>ARG), A: 1175(SER−>ARG), −2.97014 −79.3551 A: 1178(ASN−>ARG),A: 1184(ASP−>HIP), A: 1190(ALA−>MET) 20 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>MET), −2.82606 −79.2243 A: 1178(ASN−>ARG),A: 1184(ASP−>ILE), A: 1202(GLU−>ASN) 21 A: 1164(VAL−>HID), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −2.25031 −78.9106 A: 1178(ASN−>ARG),A: 1184(ASP−>MET), A: 1202(GLU−>ASN) 22 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −2.92139 −78.5547 A: 1184(ASP−>ARG),A: 1202(GLU−>ASN) 23 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ILE), −2.69119 −78.3961 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP),A: 1202(GLU−>ASN) 24 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ILE), −2.59426 −77.2938 A: 1178(ASN−>ARG), A: 1184(ASP−>LEU),A: 1202(GLU−>ASN) 25 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.93001 −77.1471 A: 1178(ASN−>ARG), A: 1184(ASP−>MET),A: 1190(ALA−>MET) 26 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.03167 −76.9135 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP),A: 1202(GLU−>ASN) 27 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ILE), −1.74416 −76.5694 A: 1178(ASN−>ARG), A: 1184(ASP−>ARG),A: 1202(GLU−>ASN) 28 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −3.13567 −76.5467 A: 1178(ASN−>ARG), A: 1184(ASP−>ASN),A: 1202(GLU−>ASN) 29 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.31438 −76.4215 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP),A: 1202(GLU−>ASN) 30 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −3.12762 −76.3308 A: 1178(ASN−>ARG), A: 1184(ASP−>ALA),A: 1202(GLU−>ASN) 31 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.85122 −76.1498 A: 1178(ASN−>ARG), A: 1184(ASP−>VAL),A: 1202(GLU−>ASN) 32 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.87705 −76.0657 A: 1178(ASN−>ARG), A: 1184(ASP−>ILE),A: 1190(ALA−>MET) 33 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.72771 −76.0509 A: 1178(ASN−>ARG), A: 1184(ASP−>ARG)34 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ILE), −2.62087−75.9333 A: 1178(ASN−>ARG), A: 1184(ASP−>MET), A: 1202(GLU−>ASN) 35 A:1164(VAL−>HID), A: 11.73(ASN−>ARG), A: 1175(SER−>MET), −1.93485 −75.8089A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), A: 1202(GLU−>ASN) 36 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.69484 −75.7216A: 1178(ASN−>ARG), A: 1184(ASP−>ARG), A: 1190(ALA−>MET) 37 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.88096 −75.6159A: 1178(ASN−>ARG), A: 1184(ASP−>THR), A: 1202(GLU−>ASN) 38 A:1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.22244 −75.6088A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), A: 1202(GLU−>ASN) 39 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.91395 −75.3534A: 1178(ASN−>ARG), A: 1184(ASP−>LYS), A: 1202(GLU−>ASN) 40 A:1164(VAL−>LYS), A: 1175(SER−>MET), A: 1178(ASN−>ARG), −2.13032 −75.31 A:1184(ASP−>ARG), A: 1202(GLU−>ASN) 41 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>MET), −2.87163 −75.2573 A: 1178(ASN−>ARG),A: 1184(ASP−>HIE), A: 1202(GLU−>ASN) 42 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>MET), −2.67835 −75.14 A: 1178(ASN−>ARG), A:1184(ASP−>HIP), A: 1190(ALA−>MET) 43 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ILE), −2.59772 −75.0713 A: 1178(ASN−>ARG),A: 1184(ASP−>ILE), A: 1202(GLU−>ASN) 44 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −3.16938 −75.0555 A: 1178(ASN−>ARG),A: 1184(ASP−>ARG), A: 1199(ASP−>VAL) 45 A: 1164(VAL−>HID), A:1175(SER−>ARG), A: 1178(ASN−>ARG), −1.52503 −75.0103 A: 1184(ASP−>ARG),A: 1202(GLU−>ASN) 46 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>MET), −1.98351 −74.5899 A: 1178(ASN−>ARG), A: 1184(ASP−>MET),A: 1202(GLU−>ASN) 47 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.0849 −74.4922 A: 1178(ASN−>ARG), A: 1184(ASP−>ARG),A: 1190(ALA−>MET) 48 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.27884 −74.4681 A: 1178(ASN−>ARG), A: 1184(ASP−>THR),A: 1202(GLU−>ASN) 49 A: 1164(VAL−>LYS), A: 1175(SER−>ARG), A:1178(ASN−>ARG) −2.40213 −74.4269 A: H84(ASP−>MET), A: 1202(GLU−>ASN) 50A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.26962−74.1192 A: 1178(ASN−>ARG), A: 1184(ASP−>HIE), A: 1202(GLU−>ASN) 51 A:1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.28673 −74, 0204A: 1178(ASN−>ARG), A: 1184(ASP−>LYS), A: 1202(GLU−>ASN) 52 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.58518 −73.9703A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), A: 1190(ALA−>MET) 53 A:1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.07138 −73.961A: 1178(ASN−>ARG), A: 1184(ASP−>HIP), A: 1190(ALA−>MET) 54 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.64144 −73.8811A: 1184(ASP−>ARG), A: 1202(GLU−>ASN) 55 A: 1164(VAL−>HID), A:1173(ASN−>ARG), A: 1175(SER−>MET), −1.93729 −73.5944 A: 1178(ASN−>ARG),A: 1184(ASP−>ILE), A: 1202(GLU−>ASN) 56 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −2.90375 −73.0497 A: 1178(ASN−>ARG),A: 1184(ASP−>VAL), A: 1190(ASA−>MET) 57 A: 1164(VAL−>MHP), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −2.03164 −73.0418 A: 1184(ASP−>ARG),A: 1202(GLU−>ASN) 58 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.63835 −72.757 A: 1178(ASN−>ARG), A: 1184(ASP−>MET),A: 1190(ALA−>MET) 59 A: 1164(VAL−>LYS), A: 1175(SER−>ILE), A:1178(ASN−>ARG), −1.87427 −72.6957 A: 1184(ASP−>ARG), A: 1202(GLU−>ASN)60 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −3.16475−72.6793 A: 1178(ASN−>ARG), A: 1184(ASP−>PHE), A: 1202(GLU−>ASN) 61 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.8657 −72.465 A:1178(ASN−>ARG), A: 1184(ASP−>CYS), A: 1202(GLU−>ASN) 62 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.93048 −72.4396A: 1178(ASN−>ARG), A: 1184(ASP−>THR), A: 1190(ALA−>MET) 63 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.85352 −72.24 A:1178(ASN−>ARG), A: 1184(ASP−>ASN), A: 1202(GLU−>ASN) 64 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.90996 −72.205A: 1184(ASP−>MET), A: 1202(GLU−>ASN) 65 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −3.1514 −72.1371 A: 1178(ASN−>ARG),A: 1184(ASP−>CYS), A: 1202(GLU−>ASN) 66 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>MET), −2.83939 −72.0255 A: 1178(ASN−>ARG),A: 1184(ASP−>ALA), A: 1202(GLU−>ASN) 67 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ILE), −2.62152 −72.0013 A: 1178(ASN−>ARG),A: 1184(ASP−>VAL), A: 1202(GLU−>ASN) 68 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>MET), −2.43883 −71.8836 A: 1178(ASN−>ARG),A: 1184(ASP−>ARG) 69 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.9478 −71.8725 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP),A: 1199(ASP−>VAL) 70 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.58851 −71.7534 A: 1178(ASN−>ARG), A: 1184(ASP−>ILE),A: 1190(ALA−>MET) 71 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.03125 −71.7529 A: 1178(ASN−>ARG), A: 1184(ASP−>MET),A: 1190(ALA−>MET) 72 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.78057 −71.7522 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP)73 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ILE), −2.47592−71.6783 A: 1178(ASN−>ARG), A: 1184(ASP−>ARG), A: 1190(ALA−>MET) 74 A:1164(VAL−>LYS), A: 1174(SER−>MET), A: 1178(ASN−>ARG), −2.1891 −71.5334A: 1184(ASP−>HIP), A: 1202(GLU−>ASN) 75 A: 1164(VAL−>LYS), A:1175(SER−>ARG), A: 1178(ASN−>ARG), −2.47533 −71.5042 A: 1184(ASP−>HIP),A: 1202(GLU−>ASN) 76 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ILE), −2.65276 −71.4651 A: 1178(ASN−>ARG), A: 1184(ASP−>THR),A: 1202(GLU−>ASN) 77 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.26304 −71.3236 A: 1178(ASN−>ARG), A: 1184(ASP−>CYS),A: 1202(GLU−>ASN) 78 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −0.516825 −71.3124 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP),A: 1199(ASP−>VAL) 79 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ILE), −2.6856 −71.2206 A: 1178(ASN−>ARG), A: 1184(ASP−>LYS),A: 1202(GLU−>ASN) 80 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ILE), −2.46309 −71.1379 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP),A: 1190(ALA−>MET) 81 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.87288 −70.6398 A: 1178(ASN−>ARG), A: 1184(ASP−>TRP),A: 1202(GLU−>ASN) 82 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −1.83906 −70.5481 A: 1178(ASN−>ARG), A: 1184(ASP−>ARG)83 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −1.96153−70.5143 A: 1178(ASN−>ARG), A: 1184(ASP−>VAL), A: 1202(GLU−>ASN) 84 A:1164(VAL−>LYS), A: 1175(SER−>ARG), A: 1178(ASN−>ARG), −2.3792 −70.491 A:1184(ASP−>LEU), A: 1202(GLU−>ASN) 85 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −3.18508 −70.3237 A: 1178(ASN−>ARG),A: 1184(ASP−>TRP), A: 1202(GLU−>ASN) 86 A: 1164(VAL−>LYS), A:1175(SER−>MET), A: 1178(ASN−>ARG), −2.09248 −70.3027 A: 1184(ASP−>LEU),A: 1202(GLU−>ASN) 87 A: 1164(VAL−>LYS), A: 1175(SER−>ARG), A:1178(ASN−>ARG), −2.25074 −70.264 A: 1184(ASP−>ARG), A: 1190(ALA−>MET) 88A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.24818−70.2603 A: 1178(ASN−>ARG), A: 1184(ASP−>VAL), A: 1202(GLU−>ASN) 89 A:1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −1.79539 −70.1623A: 1178(ASN−>ARG), A: 1184(ASP−>ARG), A: 1190(ALA−>MET) 90 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.69125 −70.0385A: 1184(ASP−>HIP), A: 1202(GLU−>ASN) 91 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ILE), −2.40499 −70.0128 A: 1184(ASP−>ARG),A: 1202(GLU−>ASN) 92 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.97927 −70.0001 A: 1184(ASP−>HIP), A: 1202(GLU−>ASN)93 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −1.99143−69.9823 A: 1178(ASN−>ARG), A: 1184(ASP−>THR), A: 1202(GLU−>ASN) 94 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.71599 −69.806A: 1178(ASN−>ARG), A: 1184(ASP−>MET) 95 A: 1164(VAL−>LYS), A:1175(SER−>ARG), A: 1178(ASN−>ARG), −2.23843 −69.7272 A: 1184(ASP−>HIP),A: 1190(ALA−>MET) 96 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>MET), −1.77931 −69.5775 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP),A: 1190(ALA−>MET) 97 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.89081 −69.4973 A: 1178(ASN−>ARG), A: 1184(ASP−>LEU),A: 1199(ASP−>VAL) 98 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.26314 −69.4945 A: 1178(ASN−>ARG), A: 1184(ASP−>TRP),A: 1202(GLU−>ASN) 99 A: 1164(VAL−>HID), A: 1175(SER−>MET), A:1178(ASN−>ARG), −1.24082 −69.4942 A: 1184(ASP−>ARG), A: 1202(GLU−>ASN)100 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −3.17673−69.1654 A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), A: 1199(ASP−>VAL) 101 A:1164(VAL−>LYS), A: 1175(SER−>MET), A: 1178(ASN−>ARG), −2.14073 −69.0781A: 1184(ASP−>MET), A: 1202(GLU−>ASN) 102 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −2.89142 −68.8574 A: 1178(ASN−>ARG),A: 1184(ASP−>ALA), A: 1190(ALA−>MET) 103 A: 1164(VAL−>HID), A:1175(SER−>ARG), A: 1178(ASN−>ARG), −1.51398 −68.7879 A: 1184(ASP−>MET),A: 1202(GLU−>ASN) 104 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.87331 −68.7805 A: 1184(ASP−>LEU), A: 1202(GLU−>ASN)105 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ILE), −2.42088−68.7319 A: 1178(ASN−>ARG), A: 1184(ASP−>MET), A: 1190(ALA−>MET) 106 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.61056 −68.656A: 1178(ASN−>ARG), A: 1184(ASP−>VAL), A: 1190(ALA−>MET) 107 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.59308 −68.5377A: 1184(ASP−>LEU), A: 1202(GLU−>ASN) 108 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>MET), −2.87633 −68.3844 A: 1178(ASN−>ARG),A: 1184(ASP−>PHE), A: 1202(GLU−>ASN) 109 A: 1164(VAL−>HID), A:1173(ASN−>ARG), A: 1175(SER−>MET), −1.75278 −68.2442 A: 1184(ASP−>ARG),A: 1202(GLU−>ASN) 110 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.64184 −68.1336 A: 1178(ASN−>ARG), A: 1184(ASP−>THR),A: 1190(ALA−>MET) 111 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ILE), −2.62486 −68.0901 A: 1178(ASN−>ARG), A: 1184(ASP−>ASN),A: 1202(GLU−>ASN) 112 A: 1164(VAL−>LYS), A: 1175(SER−>MET), A:1178(ASN−>ARG), −2.09451 −68.0828 A: 1184(ASP−>ILE), A: 1202(GLU−>ASN)113 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), _?498?5−68.0702 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP) 114 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −274988 −68.0679 A: 1184(ASP−>ARG),A: 1190(ALA−>MET) 115 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.67546 −67.9832 A: 1178(ASN−>ARG), A: 1184(ASP−>LYS),A: 1190(ALA−>MET) 116 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.63539 −67.8022 A: 1178(ASN−>ARG), A: 1184(ASP−>HIE),A: 1190(ALA−>MET) 117 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ILE), −2.21033 −67.7376 A: 1178(ASN−>ARG), A: 1184(ASP−>ARG)118 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ILE), −2.36989−67.7095 A: 1178(ASN−>ARG), A: 1184(ASP−>ILE), A: 1190(ALA−>MET) 119 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.95321 −67.5733A: 1178(ASN−>ARG), A: 1184(ASP−>TRP), A: 1190(ALA−>MET) 120 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.92368 −67.4455A: 1178(ASN−>ARG), A: 1184(ASP−>HIE), A: 1190(ALA−>MET) 121 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.92977 −67.4121A: 1178(ASN−>ARG), A: 1184(ASP−>LYS), A: 1190(ALA−>MET) 122 A:1164(VAL−>LYS), A: 1175(SER−>ARG), A: 1178(ASN−>ARG), −2.19916 −67.4095A: 1184(ASP−>MET), A: 1190(ALA−>MET) 123 A: 1164(VAL−>LYS), A:1173(ASX−>ARG), A: 1175(SER−>ARG), −2.73459 −67.3546 A: 1184(ASP−>HIP),A: 1190(ALA−>MET) 124 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>MET), −1.73996 −67.2204 A: 1178(ASN−>ARG), A: 1184(ASP−>MET),A: 1190(ALA−>MET) 125 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.27028 −67.1836 A: 1178(ASN−>ARG), A: 1184(ASP−>PHE),A: 1202(GLU−>ASN) 126 A: 1164(VAL−>HID), A: 1165(ASP−>ARG), A:1173(ASN−>ARG), −3.09006 −66.9395 A: 1175(SER−>MET), A: 1178(ASN−>ARG),A: 1184(ASP−>MET) 127 A: 1164(VAL−>LYS), A: 1165(ASP−>ARG), A:1173(ASN−>ARG), −3.928 −66.9124 A: 1175(SER−>MET), A: 1178(ASN−>ARG), A:1184(ASP−>MET) 128 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.40174 −66.8723 A: 1178(ASN−>ARG), A: 1184(ASP−>LEU)129 A: 1164(VAL−>LYS), A: 1165(ASP−>MET), A: 1173(ASN−>ARG), −3.5736−66.7995 A: 1175(SER−>ARG), A: 1178(ASN−>ARG), A: 1184(ASP−>HIP) 130 A:1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −1.95052 −66.3943A: 1178(ASN−>ARG), A: 1184(ASP−>ALA), A: 1202(GLU−>ASN) 131 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.59701 −66.3285A: 1184(ASP−>ILE), A: 1202(GLU−>ASN) 132 A: 1164(VAL−>HID), A:1173(ASN−>ARG), A: 1175(SER−>MET), −1.55026 −66.2486 A: 1178(ASN−>ARG),A: 1184(ASP−>ARG) 133 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.05838 −66.2385 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP),A: 1199(ASP−>VAL) 134 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>MET), −1.68924 −66.1946 A: 1178(ASN−>ARG), A: 1184(ASP−>ILE),A: 1190(ALA−>MET) 135 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.23545 −66.1903 A: 1178(ASN−>ARG), A: 1184(ASP−>ALA),A: 1202(GLU−>ASN) 136 A: 1164(VAL−>LYS), A: 1165(ASP−>SER), A:1173(ASN−>ARG), −3.14599 −65.5882 A: 1175(SER−>MET), A: 1178(ASN−>ARG),A: 1184(ASP−>LEU) 137 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ILE), −1.56168 −65.5328 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP),A: 1190(ALA−>MET) 138 A: 1164(VAL−>HID), A: 1165(ASP−>SER), A:1173(ASN−>ARG), −2.29549 −65.4798 A: 1175(SER−>MET), A: 1178(ASN−>ARG),A: 1184(ASP−>LEU) 139 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ILE), −2.66177 −65.3458 A: 1178(ASN−>ARG), A: 1184(ASP−>LEU),A: 1199(ASP−>VAL) 140 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.61782 −65.2462 A: 1178(ASN−>ARG), A: 1184(ASP−>ASN),A: 1190(ALA−>MET) 141 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.446 −65.1794 A: 1178(ASN−>ARG), A: 1184(ASP−>MET) 142A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.72561−65.1716 A: 1178(ASN−>ARG), A: 1184(ASP−>LEU) 143 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −3.15618 −65.1475 A: 1178(ASN−>ARG),A: 1184(ASP−>VAL), A: 1199(ASP−>VAL) 144 A: 1164(VAL−>LYS), A:1175(SER−>MET), A: 1178(ASN−>ARG), −1.96398 −64.9665 A: 1184(ASP−>ARG),A: 1190(ALA−>MET), 145 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.62551 −64.964 A: 1178(ASN−>ARG), A: 1184(ASP−>CYS),A: 1190(ALA−>MET) 146 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.7056 −64.9267 A: 1184(ASP−>MET), A: 1190(ALA−>MET)147 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.90685−64.9043 A: 1178(ASN−>ARG), A: 1184(ASP−>ASN), A: 1190(ALA−>MET) 148 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.90094 −64.6852A: 1178(ASN−>ARG), A: 1184(ASP−>HIE), A: 1199(ASP−>VAL) 149 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.40386 −64.6453A: 1178(ASN−>ARG), A: 1184(ASP−>ILE) 150 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −2.91451 −64.6249 A: 1178(ASN−>ARG),A: 1184(ASP->CYA), A: 1190(ALA−>MET) 151 A: 1164(VAL−>LYS), A:1175(SER−>ARG), A: 1178(ASN−>ARG), −2.4356 −64.5724 A: 1184(ASP−>ARG),A: 1199(ASP−>VAL) 152 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG),A:1175(SER−>MET), −2.60191 −64.5258 A: 1178(ASN−>ARG), A:1184(ASP−>ALA), A: 1190(ALA−>MET) 153 A: 1164(VAL−>LYS), A:1175(SER−>MET), A: 1178(ASN−>ARG), −2.14927 −64.4745 A: 1184(ASP−>THR),A: 1202(GLU−>ASN) 154 A: 1164(VAL−>LYS), A: 1175(SER−>ARG), A:1178(ASN−>ARG), −2.46702 −64.3537 A: 1184(ASP−>LYS), A: 1202(GLU−>ASN)155 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −3.18554−64.3519 A: 1178(ASN−>ARG), A: 1184(ASP−>HIE), A: 1199(ASP−>VAL) 156 A:1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>ARG), −1.9736 −64.3502A: 1190(ALA−>MET), A: l194(ASN−>LEU), A: 1199(ASP−>HIE) 157 A:1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −1.82802 −64.3376A: 1178(ASN−>ARG), A: 1184(ASP−>MED. 158 A: 1164(VAL−>LYS), A:1175(SER−>MET), A: 1178(ASN−>ARG), −1.94693 −64.3347 A: 1184(ASP−>HIP),A: 1190(ALA−>MET) 159 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ILE), −2.64384 −64.2248 A: 1178(ASN−>ARG), A: 1184(ASP−>PHE),A: 1202(GLU−>ASN) 160 A: 1164(VAL−>HID), A: 1175(SER−>ARG), A:1178(ASN−>ARG), −1.57318 −64.0203 A: 1184(ASP−>LYS), A: 1202(GLU−>ASN)161 A: 1164(VAL−>LYS), A: 1175(SER−>ILE), A: 1178(ASN−>ARG), −2.29523−63.9817 A: 1184(ASP−>ARG), A: 1190(ALA−>MET), A: 1194(ASN−>HIP) 162 A:1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.00221 −63.8718A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), A: 1199(ASP−>VAL) 163 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ILE), −2.41927 −63.7744A: 1178(ASN−>ARG), A: 1184(ASP−>HIE), A: 1190(ALA−>MET) 164 A:1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.27711 −63.5811A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), A: 1199(ASP−>VAL) 165 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.46413 −63.3576A: 1184(ASP−>ARG), A: 1190(ALA−>MET) 166 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>MET), −2.91376 −63.2499 A: 1178(ASN−>ARG),A: 1184(ASP−>THR), A: 1199(ASP−>VAL) 167 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>MET), −2.64001 −63.2023 A: 1178(ASN−>ARG),A: 1184(ASP−>TRP), A: 1190(ALA−>MET) 168 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −2.93736 −63.0834 A: 1184(ASP−>ARG),A: 1199(ASP−>VAL) 169 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.96397 −62.8659 A: 1184(ASP−>LYS), A: 1202(GLU−>ASN)170 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.68914−62.8447 A: 1184(ASP−>LYS), A: 1202(GLU−>ASN) 171 A: 1164(VAL−>HID), A:1173(ASN−>ARG), A: 1175(SER−>ARG), −1.99285 −62.8164 A: 1178(ASN−>ARG),A: 1184(ASP−>VAL), A: 1190(ALA−>MET) 172 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>MET), −2.65492 −62.7923 A: 1184(ASP−>THR),A: 1202(GLU−>ASN) 173 A: 1164(VAL−>LYS), A: 1165(ASP−>ARG), A:1173(ASN−>HIP), −3.88582 −62.7674 A: 1175(SER−>MET), A: 1178(ASN−>ARG),A: 1184(ASP−>MET) 174 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>MET), −1.9833 −62.7382 A: 1178(ASN−>ARG), A: 1184(ASP−>PHE),A: 1202(GLU−>ASN) 175 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.44671 −62.5372 A: 1184(ASP−>HIP), A: 1190(ALA−>MET)176 A: 1164(VAL−>LYS), A: 1165(ASP−>ARG), A: 1173(ASN−>ARG), −3.67967−62.341 A: 1175(SER−>MET), A: 1178(ASN−>MET), A-1184(ASP−>MET) 177 A:1164(VAL−>LYS), A: 1175(SER−>ILE), A: 1178(ASN−>ARG), −1.71426 −62.3026A: 1184(ASP−>ARG), A: 1190(ALA−>MET) 178 A: 1164(VAL−>LYS), A:1175(SER−>MET), A: 1178(ASN−>ARG), −1.90748 −61.8435 A: 1184(ASP−>MET),A: 1190(ALA−>MET) 179 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A:1184(ASP−>ARG), −2.34314 −61.5862 A: 1190(ALA−>MET), A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 180 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −1.87272 −61.4739 A: 1178(ASN−>ARG), A: 1184(ASP−>HIP)181 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −1.54951−61.2732 A: 1178(ASN−>ARG), A: 1184(ASP−>LEU) 182 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ILE), −2.40038 −61.2207 A: 1178(ASN−>ARG),A: 1184(ASP−>ASN), A: 1190(ALA−>MET) 183 A: 1164(VAL−>LYS), A:1165(ASP−>SER), A: 1173(ASN−>HIP), −3.10441 −61.1722 A: 1175(SER−>MET),A: 1178(ASN−>ARG), A: 1184(ASP−>LEU) 184 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ILE), −2.22859 −61.1545 A: 1178(ASN−>ARG),A: 1184(ASP−>MET) 185 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A:1184(ASP−>HIP), −1.93857 −61.1541 A: 1190(ALA−>MET), A: 1194(ASN−>LEU),A: 1199(ASP−>HIE) 186 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −3.15493 −61.1074 A: 1178(ASN−>ARG), A: 1184(ASP−>ALA),A: 1199(ASP−>VAL) 187 A: 1164(VAL−>HID), A: 1165(ASP−>SER), A:1173(ASN−>HIP), −2.25286 −61, 056 A: 1175(SER−>MET), A: 1178(ASN−>ARG),A: 1184(ASP−>LEU) 188 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.45804 −61.042 A: 1178(ASN−>ARG), A: 1184(ASP−>THR)189 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>HIP), −2.32895−60.9551 A: 1190(ALA−>MET), A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 190 A:1164(VAL−>LYS), A: 1165(ASP−>SER), A: 1173(ASN−>ARG), −2.90263 −60.9092A: 1175(SER−>MET), A: 1178(ASN−>MET), A: 1184(ASP−>LEU) 191 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.63509 −60.9004A: 1178(ASN−>ARG), A: 1184(ASP−>PHE), A: 1190(ALA−>MET) 192 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.49057 −60.8806A: 1178(ASN−>ARG), A: 1184(ASP−>LYS) 193 A: 1164(VAL−>LYS), A:1175(SER−>MET), A: 1178(ASN−>ARG), −2.10775 −60.8756 A: 1184(ASP−>ALA),A: 1202(GLU−>ASN) 194 A: 1164(VAL−>LYS), A: 1165(ASP−>ARG), A:1173(ASN−>ARG), −3.57056 −60.8698 A: 1175(SER−>MET), A: 1178(ASN−>GLN),A: 1184(ASP−>MET) 195 A: 1164(VAL−>LYS), A: 1175(SER−>MET), A:1178(ASN−>ARG), −2.21569 −60.8561 A: 1184(ASP−>HIP), A: 1199(ASP−>VAL)196 A: 1164(VAL−>LYS), A: 1175(SER−>ARG), A: 1178(ASN−>ARG), −2.50428−60.837 A: 1184(ASP−>HIP), A: 1199(ASP−>VAL) 197 A: 1164(VAL−>LYS), A:1175(SER−>MET), A: 1178(ASN−>ARG), −1.85736 −60.8231 A: 1184(ASP−>ILE),A: 1190(ALA−>MET) 198 A: 1164(VAL−>HID), A: 1165(ASP−>SER), A:1173(ASN−>ARG), −2.0521 −60.8007 A: 1175(SER−>MET), A: 1178(ASN−>MET),A: 1184(ASP−>LEU) 199 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −2.77682 −60.3913 A: 1178(ASN−>ARG), A: 1184(ASP−>LYS)200 A: 1164(VAL−>LYS), A: 1175(SER−>ILE), A: 1178(ASN−>MET), −2.0909−60.035 A: 1184(ASP−>ARG), A: 1190(ALA−>MET), A: 1194(ASN−>HIP) 201 A:1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), −2.23391 −60, 0169A: 1190(ALA−>MET), A: l194(ASN−>HIP), A: 1199(ASP−>HIE) 202 A:1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), −1.8501 −59.9887A: 1190(ALA−>MET), A: 1194(ASN−>LEU), A: 1199(ASP−>HIE), 203 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.41103 −59.8778A: 1184(ASP−>MET), A: 1190(ALA−>MET) 204 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ILE), −2.24587 −59.5636 A: 1184(ASP−>ARG),A: 1190(ALA−>MET) 205 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −1.88721 −59.5589 A: 1178(ASN−>ARG), A: 1184(ASP−>LYS)206 A: 1164(VAL−>LYS), A: 1165(ASP−>SER), A: 1173(ASN−>ARG), −2.79297−59.4426 A: 1175(SER−>MET), A: 1178(ASN−>GLN), A: 1184(ASP−>LEU) 207 A:1164(VAL−>HID), A: 1165(ASP−>SER), A: 1173(ASN−>ARG), −1.941 −59.3255 A:1175(SER−>MET), A: 1178(ASN−>GLN), A: 1184(ASP−>LEU) 208 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.62115 −59.299A: 1184(ASP−>ALA), A: 1202(GLU−>ASN) 209 A: 1164(VAL−>LYS), A:1175(SER−>ILE), A: 1178(ASN−>ARG), −1.65888 −59.2057 A: 1184(ASP−>MET),A: 1190(ALA−>MET) 210 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.35596 −58.7707 A: 1184(ASP−>ILE), A: 1190(ALA−>MET)211 A: 1164(VAL−>HID), A: 1175(SER−>ARG), A: 1178(ASN−>ARG), −1.32787−58.6361 A: 1184(ASP−>HIP), A: 1190(ALA−>MET) 212 A: 1164(VAL−>HID), A:1178(ASN−>ARG), A: 1184(ASP−>ARG), −1.07475 −58.6274 A: 1190(ALA−>MET),A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 213 A: 1164(VAL−>LYS), A:1175(SER−>ARG), A: 1178(ASN−>ARG), −2.44453 −58.5548 A: 1184(ASP−>LEU),A: 1199(ASP−>VAL) 214 A: 1164(VAL−>LYS), A: 1175(SER−>1LE), A:1178(ASN−>GLN), −2.00642 −58.5309 A: 1184(ASP−>ARG), A: 1190(ALA−>MET),A: 1194(ASN−>HIP) 215 A: 1164(VAL−>LYS), A: 1175(SER−>MET), A:1178(ASN−>ARG), −2.15956 −58.3528 A: 1184(ASP−>LEU), A: 1199(ASP−>VAL)216 A: 1164(VAL−>HID), A: 1175(SER−>ILE), A: 1178(ASN−>ARG), −1.39562−58.2628 A: 1184(ASP−>ARG), A: 1190(ALA−>MET), A: 1194(ASN−>HIP) 217 A:1164(VAL−>LYS), A: 1175(SER−>ILE), A: 1178(ASN−>ARG), 0.571404 −58.22 A:1184(ASP−>ARG), A: 1190(ALA−>ARG), A: 1194(ASN−>HIP) 218 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.90235 −57.7798A: 1178(ASN−>ARG), A: 1184(ASP−>PHE), A: 1199(ASP−>VAL) 219 A:1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>ILE), −1.85326 −57.7746A: 1190(ALA−>MET), A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 220 A:1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>ILE), −2.2333 −57.7722A: 1190(ALA−>MET), A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 221 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.72911 −57.5653A: 1178(ASN−>ARG), A: 1184(ASP−>CYS) 222 A: 1164(VAL−>LYS), A:1178(ASN−>ARG), A: 1184(ASP−>ARG), −2.54591 −57.4777 A: 1190(ALA−>MET),A: 1194(ASN−>HIP) 223 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A:1175(SER−>MET), −2.41707 −57.4453 A: 1178(ASN−>ARG), A: 1184(ASP−>ALA)224 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.02148−57.3468 A: 1178(ASN−>ARG), A: 1184(ASP−>TRP), A: 1190(ALA−>MET) 225 A:1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>ARG), −2.70191 −57.1236A: 1178(ASN−>ARG), A: 1184(ASP−>ALA) 226 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A:1175(SER−>ARG), −2.93847 −57.0341 A: 1184(ASP−>LEU),A: 1199(ASP−>VAL) 227 A: 1164(VAL−>HID), A: 1173(ASN−>ARG), A:1175(SER−>ARG), −1, 81954 −56.962 A: 1184(ASP−>HIP), A: 1190(ALA−>MET)228 A: 1164(VAL−>LYS), A: 1173(ASN−>ARG), A: 1175(SER−>MET), −2.67239−56.9136 A: 1184(ASP−>LEU), A: 1199(ASP−>VAL) 229 A: 1164(VAL−>LYS), A:1165(ASP−>ARG), A: 1173(ASN−>LYS), −3.77371 −56.43 A: 1175(SER−>MET), A:1178(ASN−>ARG), A: 1184(ASP−>MET) 230 A: 1164(VAL−>LYS), A:1178(ASN−>ARG), A: 1184(ASP−>ARG), −1.7807 −56.401 A: 1194(ASN−>LEU), A:1199(ASP−>HIE) 231 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A:1184(ASP−>ARG), −1.5806 −56.2086 A: 1190(ALA−>MET), A: 1194(ASN−>LEU)232 A: 1164(VAL−>LYS), A: 1165(ASP−>ARG), A: 1173(ASN−>ARG), −3.93351−56.0908 A: 1178(ASN−>ARG), A: 1184(ASP−>MET) 233 A: 1164(VAL−>LYS), A:1173(ASN−>ARG), A: 1175(SER−>ILE), −2.19329 −56.0845 A: 1184(ASP−>MET),A: 1190(ALA−>MET) 234 A: 1164(VAL−>HID), A: 1178(ASN−>ARG), A:1184(ASP−>ARG), −1.44375 −55.8382 A: 1190(ALA−>MET), A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 235 A: 1164(VAL−>LYS), A: 1175(SER−>ILE), A:1178(ASN−>MET), −1.57359 −56.6665 A: 1184(ASP−>ARG), A: 1190(ALA−>MET)236 A: 1164(VAL−>HID), A: 1178(ASN−>ARG), A: 1184(ASP−>HIP), −1.04398−55.429 A: 1190(ALA−>MET), A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 237 A:1164(VAL−>HID), A: 1178(ASN−>ARG), A: 1184(ASP−>HIP), −1.42994 −55.2321A: 1190(ALA−>MET), A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 238 A:1164(VAL−>LYS), A: 1165(ASP−>SER), A: 1173(ASN−>LYS), −2.99354 −54.7792A: 1175(SER−>MET), A: 1178(ASN−>ARG), A: 1184(ASP−>LEU) 239 A:1164(VAL−>LYS), A: 1165(ASP−>SER), A: 1173(ASN−>ARG), −3.15365 −54.7765A: 1178(ASN−>ARG), A: 1184(ASP−>LEU) 240 A: 1164(VAL−>HID), A:1165(ASP−>SER), A: 1173(ASN−>ARG), −2.29925 −54.6827 A: 1178(ASN−>ARG),A: 1184(ASP−>LEU) 241 A: 1164(VAL−>HID), A: 1165(ASP−>SER), A:1173(ASN−>LYS), −2.14137 −54.6386 A: 1175(SER−>MET), A: 1178(ASN−>ARG),A: 1184(ASP−>LEU) 242 A: 1164(VAL−>LYS), A: 1173(ASN−>LYS), A:1175(SER−>MET), −2.29027 −54.6029 A: 1178(ASN−>ARG), A: 1184(ASP−>MET)243 A: 1164(VAL−>HID), A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), −1.33444−54.2878 A: 1190(ALA−>MET), A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 244 A:1164(VAL−>HID), A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), −0.950624 −54.2595A: 1190(ALA−>MET), A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 245 A:1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>THR), −2.29015 −54.1733A: 1190(ALA−>MET), A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 246 A:1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>THR), −1.90838 −54.1509A: 1190(ALA−>MET), A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 247 A:1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>HIE), −2.28396 −53.8287A: 1190(ALA−>MET), A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 248 A:1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>LYS), −2.31945 −53.6853A: 1190(ALA−>MET), A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 249 A:1164(VAL−>HID), A: 1165(ASP−>ARG), A: 1173(ASN−>ARG), −2.81062 −53.396A: 1175(SER−>MET), A: 1178(ASN−>ARG) 250 A: 1164(VAL−>LYS), A:1165(ASP−>ARG), A: 1173(ASN−>ARG), −3.6499 −53.3685 A: 1175(SER−>MET),A: 1178(ASN−>ARG) 251 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A:1184(ASP−>ARG), −2.13751 −53.24 A: 1194(ASN−>HIP), A: 1199(ASP−>ILE) 252A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>HIP), −1.74878−53.2001 A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 253 A: 1164(VAL−>HID), A:1173(ASN−>ARG), A: 1175(SER−>ILE), −1.32956 −53.1974 A: 1184(ASP−>HIP),A: 1190(ALA−>MET) 254 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A:1184(ASP−>HIP), −1.93039 −53.1422 A: 1190(ALA−>MET), A: 1194(ASN−>HIP)255 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>HIP), −1.55086−52.972 A: 1190(ALA−>MET), A: 1194(ASN−>LEU) 256 A: 1164(VAL−>LYS), A:1178(ASN−>ARG), A: 1184(ASP−>HIP), −2.12473 −52.6295 A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 257 A: 1164(VAL−>LYS), A: 1165(ASP−>SER), A:1173(ASN−>ARG), −2.88468 −52.1912 A: 1175(SER−>MET), A: 1178(ASN−>ARG)258 A: 1164(VAL−>HID), A: 1165(ASP−>SER), A: 1173(ASN−>ARG), −2.03178−52.0905 A: 1175(SER−>MET), A: 1178(ASN−>ARG) 259 A: 1164(VAL−>LYS), A:1178(ASN−>ARG), A: 1184(ASP−>LEU), −1.64748 −52.0075 A: 1194(ASN−>LEU),A: 1199(ASP−>HIE) 260 A: 1164(VAL−>LYS), A: 1168(ASP−>GLN), A:1178(ASN−>ARG), −2.59663 −51.9118 A: 1184(ASP−>THR), A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 261 A: 1164(VAL−>LYS), A: 1184(ASP−>ARG), A:1190(ALA−>MET), −1.72345 −51.7064 A: 1194(ASN−>LEU), A: 1199(ASP−>HIE)262 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>LEU), −2.02591−51.6844 A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 263 A: 1164(VAL−>LYS), A:1178(ASN−>ARG), A: 1184(ASP−>LEU), −1.45716 −51.6508 A: 1190(ALA−>MET),A: 1194(ASN−>LEU) 264 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A:1184(ASP−>ASN), −2.26597 −51.3284 A: 1190(ALA−>MET), A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 265 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A:1184(ASP−>CYS), −2.27511 −51.0564 A: 1190(ALA−>MET), A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 266 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A:1184(ASP−>CYS), −1.89015 −50.9924 A: 1190(ALA−>MET), A: 1194(ASN−>LEU),A: 1199(ASP−>HIE) 267 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A:1184(ASP−>MET), −1.89218 −50.8508 A: 1190(ALA−>MET), A: 1194(ASN−>HIP)268 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>ASN), −1.87443−50.7509 A: 1190(ALA−>MET), A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 269 A:1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>ALA), −1.86726 −50.5608A: 1190(ALA−>MET), A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 270 A:1164(VAL−>LYS), A: 1184(ASP−>ARG), A: 1190(ALA−>MET), −2.09582 −49.3103A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 271 A: 1164(VAL−>LYS), A:1178(ASN−>ARG), A: 1184(ASP−>TRP), −1.90576 −49.2111 A: 1190(ALA−>MET),A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 272 A: 1164(VAL−>HID), A:1178(ASN−>ARG), A: 1184(ASP−>VAL), −1.36119 −49.0123 A: 1190(ALA−>MET),A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 273 A: 1164(VAL−>LYS), A:1184(ASP−>HIP), A: 1190(ALA−>MET), −1.69181 −48.5687 A: 1194(ASN−>LEU),A: 1199(ASP−>HIE) 274 A: 1164(VAL−>LYS), A: 1184(ASP−>HIP), A:1190(ALA−>MET), −2.07738 −48.5237 A: 1194(ASN−>HIP), A: 1199(ASP−>HIE)275 A: 1164(VAL−>HID), A: 1178(ASN−>ARG), A: 1184(ASP−>THR), −1.0066−48.4213 A: 1190(ALA−>MET), A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 276 A:1164(VAL−>LYS), A: 1168(ASP−>GLN), A: 1178(ASN−>MET), −2.39275 −47.8262A: 1184(ASP−>THR), A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 277 A:1164(VAL−>LYS), A: 1175(SER−>ILE), A: 1178(ASN−>ARG), −1.95965 −47.6444A: 1190(ALA−>MET), A: 1194(ASN−>HIP) 278 A: 1i64(VAL−>HID), A:1178(ASN−>ARG), A: 1184(ASP−>HIP), −1.03445 −47.445 A: 1190(ALA−>MET),A: 1194(ASN−>HIP) 279 A: 1164(VAL−>LYS), A: 1184(ASP−>LEU), A:1190(ALA−>MET), −1.98168 −47.1781 A: 1194(ASN−>HIP), A: 1199(ASP−>HIE)280 A: 1164(VAL−>LYS), A: 1184(ASP−>LEU), A: 1190(ALA−>MET), −1.59609−46.9553 A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 281 A: 1164(VAL−>HID), A:1178(ASN−>ARG), A: 1184(ASP−>HIP), −1.22551 −46.9187 A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 282 A: 1164(VAL−>LYS), A: 1168(ASP−>HIP), A:1178(ASN−>ARG), −2.82991 −46.5096 A: 1184(ASP−>THR), A: 1194(ASN−>LEU),A: 1199(ASP−>HIE) 283 A: 1164(VAL−>LYS), A: 1168(ASP−>HIP), A:1178(ASN−>ARG), −3.0163 −46.2756 A: 1184(ASP−>THR), A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 284 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A:1184(ASP−>THR), −1.89486 −46.2453 A: 1190(ALA−>MET), A: 1194(ASN−>HIP)285 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>THR), −1.69532−46.1835 A: 1194(ASN−>LEU), A: 1199(ASP−>HIE) 286 A: 1164(VAL−>LYS), A:1178(ASN−>ARG), A: 1184(ASP−>LYS), −1.92686 −45.9518 A: 1190(ALA−>MET),A: 1194(ASN−>HIP) 287 A: 1164(VAL−>LYS), A: 1178(ASN−>ARG), A:1184(ASP−>THR), −2.08195 −45.9496 A: 1194(ASN−>HIP), A: 1199(ASP−>H1L)288 A: 1164(VAL−>LYS), A: 1168(ASP−>GLN), A: 1178(ASN−>ARG), 0.730758−45.8112 A: 1193(LEU−>MET), A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 289 A:1164(VAL−>LYS), A: 1178(ASN−>ARG), A: 1184(ASP−>THR), −1.51284 −45.7945A: 1190(ALA−>MET), A: 1194(ASN−>LEU) 290 A: 1164(VAL−>LYS), A:1168(ASP−>GLN), A: 1178(ASN−>ARG), −2.19932 −43.9543 A: 1184(ASP−>THR),A: 1194(ASN−>HIP) 291 A: 1164(VAL−>LYS), A: 1168(ASP−>GLN), A:1178(ASN−>ARG), −2.3087 −43.3278 A: 1194(ASN−>HIP), A: 1199(ASP−>HIE)292 A: 1164(VAL−>HID), A: 1184(ASP−>HIP), A: 1190(ALA−>MET), −1.17839−42.8006 A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 293 A: 1164(VAL−>LYS), A:1168(ASP−>GLN), A: 1178(ASN−>MET), −2.53737 −41.521 A: 1193(LEU−>MET),A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 294 A: 1164(VAL−>HID), A:1178(ASN−>ARG), A: 1184(ASP−>PHE), −1.40863 −41.2912 A: 1190(ALA−>MET),A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 295 A: 1164(VAL−>LYS), A:1184(ASP−>THR), A: 1190(ALA−>MET), −1.65308 −41.1686 A: 1194(ASN−>LEU),A: 1199(ASP−>HIE) 296 A: 1164(VAL−>LYS), A: 1168(ASP−>GLN), A:1178(ASN−>GLN), −2.1701 −40.5958 A: 1193(LEU−>MET), A: 1194(ASN−>LEU),A: 1199(ASP−>HIE) 297 A: 1164(VAL−>LYS), A: 1168(ASP−>GLN), A:1178(ASN−>GLN), −2.54242 −40.2526 A: 1193(LEU−>MET), A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 298 A: 1164(VAL−>HID), A: 1165(ASP−>GLN), A:1168(ASP−>GLN), −2.15808 −36.2301 A: 1178(ASN−>GLN), A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 299 A: 1164(VAL−>LYS), A: 1165(ASP−>GLN), A:1168(ASP−>GLN), −3.00511 −35.8764 A: 1178(ASN−>GLN), A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 300 A: 1164(VAL−>LYS), A: 1165(ASP−>GLN), A:1168(ASP−>GLN), −2.62743 −35.7392 A: 1178(ASN−>GLN), A: 1194(ASN−>LEU),A: 1199(ASP−>HIE) 301 A: 1164(VAL−>LYS), A: 1168(ASP−>GLN), A:1178(ASN−>GLN), −1.83659 −35.6898 A: 1194(ASN−>LEU), A: 1199(ASP−>HIE)302 A: 1164(VAL−>HID), A: 1168(ASP−>GLN), A: 1178(ASN−>GLN), −1.64034−34.8058 A: 1193(LEU−>MET), A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 303 A:1164(VAL−>LYS), A: 1168(ASP−>GLN), A: 1178(ASN−>GLN), −2.26436 −33.9855A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 304 A: 1164(VAL−>HID), A:1168(ASP−>GLN), A: 1178(ASN−>GLN), −1.36231 −32.1643 A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 305 A: 1164(VAL−>LYS), A: 1168(ASP−>GLN), A:1178(ASN−>GLN), −2.14806 −32.0562 A: 1193(LEU−>MET), A: 1194(ASN−>HIP)306 A: 1164(VAL−>LYS), A: 1178(ASN−>GLN), A: 1193(LEU−>MET), −2.03995−31.9945 A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 307 A: 1164(VAL−>HID), A:1165(ASP−>VAL), A: 1178(ASN−>GLN), −1.60228 −30.9256 A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 308 A: 1164(VAL−>HID), A: 1165(ASP−>GLN), A:1178(ASN−>GLN), −1.64634 −29.9852 A: 1194(ASN−>HIP), A: 1199(ASP−>HIE)309 A: 1164(VAL−>LYS), A: 1165(ASP−>GLN), A: 1178(ASN−>GLN), −2.49333−29.9225 A: 1194(ASN−>HIP), A: 1199(ASP−>HIE) 310 A: 1164(VAL−>HID), A:1165(ASP−>GLN), A: 1168(ASP−>GLN), −2.10437 −28.8455 A: 1194(ASN−>HIP),A: 1199(ASP−>HIE) 311 A: 1164(VAL−>LYS), A: 1165(ASP−>GLN), A:1168(ASP−>GLN), −2.96153 −28.4493 A: 1194(ASN−>H1P), A: 1199(ASP−>HIE)312 A: 1164(VAL−>HID), A: 1165(ASP−>GLN), A: 1168(ASP−>GLN), −1.76329−2.8.0323 A: 1178(ASN−>GLN), A: 1194(ASN−>HIP) 313 A: 1164(VAL−>LYS), A:1165(ASP−>GLN), A: 1168(ASP−>GLN), −2.61085 −27.6731 A: 1178(ASN−>GLN),A: 1194(ASN−>HIP) 314 A: 1164(VAL−>HID), A: 1165(ASP−>VAL), A:1178(ASN−>GLN), −1.08433 −27.3038 A: 1199(ASP−>HIE) 315 A:1164(VAL−>HID), A: 1165(ASP−>VAL), A: 1178(ASN−>GLN), −13.5073 −24.8788A: 1194(ASN−>HIP), A: 1199(ASP−>TYR) 316 A: 1164(VAL−>HID), A:1178(ASN−>GLN), A: 1199(ASP−>HIE) −0.33034 −21.8208 317 A:1164(VAL−>HID), A: 1178(ASN−>GLN) 0.0618879 −13.28 318 A: 1164(VAL−>HID)0.110205 −5.83216

TABLE 4 Peptide Sequences for Wild Type and Mutated Peptides NumberDescription Peptide Sequence Mutations SEQ ID NO: #120 WTVDLGDISGINASVVNIQKEI WT SEQ ID NO: 1 DRLNEVAKNLNESLIDLQE #121 HighestHVLGDISGINASVVQIQKEI  5 SEQ ID NO: 2 Affinity DRLNEVAKNLHESLIYLQE #1222^(nd) Highest VDLGDISGIRAMVVRIQKEI  6 SEQ ID NO: 3 Affinity,MRLNEVAKNLNESLIDLQE High Stability #123 Highest LRLGDISGIRARVVRIQKEI  6SEQ ID NO: 4 Stability, HRLNEVAKNLNESLIDLQN High Affinity #125 HighHRLRQIRGIRARVVQIQKEI 11 SEQ ID NO: 5 Affinity WRLNEVAKLLNESLIYLQE

Example 3 Cell-Cell Fusion Assays

HEK293T is an immortalized cell line derived from a human fetal kidney.A pair of previously described 293FT-based reporter cell lines thatconstitutively express individual split reporters (DSP1-7 and DSP8-11proteins) (Wang et al, 2014) were used and maintained in Dulbecco'smodified Eagle's medium (DMEM) containing 10/fetal bovine serum (FBS)and 1 g/mL puromycin. Calu-3 cells (ATCC HTB-55) were maintained inEagle's minimum essential medium (EMEM) containing 10% fetal bovineserum (FBS). For the construction of transient transfection vectors, asynthetic DNA corresponding to the S gene of SARS-CoV-2 (NC_045512.2)was cloned into a lentiviral transfer plasmid (CD500B-1, SBI, Palo Alto,Calif., USA) and the VSV-G gene was cloned into pCAG plasmid.

The DSP assay using 293FT cells was performed as described previously(Yamamoto et al, 2020) to monitor SARS-CoV-2-S-mediated membrane fusion.Briefly, effector cells expressing SARS-CoV-2-S protein with DSP8-11,target cells expressing ACE2, and TMPRSS2 with DSP1-7 were seeded in 10cm culture dishes (4×10⁶ cells/10 ml) one day before the assay. Twohours before the DSP assay, cells were treated with 6 μM EnduRen(Promega, Madison, Wis., USA), a substrate for Renilla luciferase, toactivate EnduRen. One microliter of each peptide dissolved in dimethylsulfoxide (DMSO) was added to the 384-well plates (Greiner Bioscience,Frickenhausen, Germany). Next, 50 μl of each single-cell suspension(effector and target cells) was added to the wells using a Multidropdispenser (Thermo Fisher Scientific, Waltham, Mass., USA). Afterincubation at 37° C. for 4 h, luciferase activity was measured using aCentro xS960 luminometer (Berthold, Germany).

The three peptides #120 (SEQ ID. NO:1), #121 (SEQ ID. NO: 2) and #125(SEQ ID NO: 5) showed strong inhibition of SARS-CoV-2 Spike-mediatedcell-cell fusion with IC₅₀ values of 0.75, 0.72 and 4.4 μM,respectively. (See FIG. 1)

Example 4 SARS-CoV-2 Pseudovirus Assay

There are two routes of transmission of SARS-CoV-2, one throughendocytosis and the other through the plasma membrane. VeroE6 cells areoriginally infected with SARS-CoV-2 by the endocytosis pathway. However,induction of TMPRSS2 expression causes them to be strongly dependent onthe plasma membrane route of infection, as is the case with Calu-3 cells(Hoffmann et al, 2020).

293T cells were transfected with an expression plasmid for SARS-CoV-2-S,VSV-G, or control expression plasmid by calcium-phosphate precipitation.At 16 h post-transfection, the cells were inoculated with areplication-deficient VSV, VSV-ΔGLuci, which lacks the VSV-G gene andencodes firefly luciferase, at an MOI=1 as described previously (Tani etal, 2010). After 2 h of incubation, cells were washed with DMEM andfurther incubated for 16 h before supernatants containing thepseudotyped viral particles were harvested. Cellular debris was removedfrom the supernatants using a syringe filter with a 0.2 μm size pore(Millipore, Bedford, Mass., USA).

For an infection assay, target Calu-3 cells were seeded in 96-wellplates (5×10⁴ cells/100 dl) one day before the assay. Cells werepre-treated with peptides for 1 h before infection. Pseudotyped viralparticles were added to cells with the peptides. After 2 h ofincubation, the culture supernatant was removed, and cells were washedwith EMEM. Cells were further incubated in EMEM containing 10% FBSwithout peptides and pseudotyped viral particles. At 16 hpost-infection, luciferase activity was measured using the Bright-GloLuciferase Assay System (Promega) and Centro xS960 luminometer(Berthold).

The three peptides #120 (SEQ ID NO: 1), #121 (SEQ ID NO: 2) and #125(SEQ ID NO: 5) showed strong inhibition of SARS-CoV-2 pseudovirusinfection in Calu-3 cells with IC₅₀ values of 0.24, 0.16 and 1.2 μM,respectively. (See FIG. 2) Furthermore, peptides #120 (SEQ ID NO: 1) and#121 (SEQ ID NO: 2) showed a strong inhibition of TMPRSS2-dependentpseudovirus infection through plasma membrane in both Calu-3 cells andVeroE6-TMPRSS2 cells (FIG. 2 and FIG. 3B), but only up to 44% (#120 (SEQID NO: 1)) and 38% (#121 (SEQ ID NO: 2)) inhibition against theinfection through the endocytosis pathway in VeroE6 cells (FIG. 3A). Onthe other hand, peptide #125 (SEQ ID: NO: 5) strongly inhibited both theTMPRSS2-dependent plasma membrane pathway in VeroE6-TMPRSS2 cells andthe endocytosis pathway in VeroE6 cells with IC₅₀ values of 1.7 μM and2.4 μM, respectively (FIGS. 3A and 3B).

Example 5 SARS-CoV-2 RNA Quantification Assay

Calu-3 cells were placed at 1×10¹ cells in a 96 well plate. Cells wereincubated with SARS-CoV-2 isolated from a patient in Japan (Yamamoto etal., 2020) at a multiplicity of infection (MOI) of 0.01 in the presenceof peptides for 30 min. Then, cells were washed with fresh medium andincubated for 24 hours with the peptides. cDNA from total cellular RNAwere generated using SuperPrep® II Cell Lysis & RT Kit for qPCR (TOYOBO,Osaka, Japan) according to the manufacturer's instructions. cDNA derivedfrom SARS-CoV-2 viral RNA was measured by real-time polymerase chainreaction (PCR) using the following primers, 5′-AAATTTTGGGGACCAGGAAC-3′(SEQ ID NO: 6) and 5′-TGGCAGCTGTGTAGGTCAAC-3′ (SEQ ID NO: 7) for GAPDHand 5′-GCACCGTCAAGGCTGAGAAC-3′ (SEQ ID NO: 8) and 5′-TGGTGAAGACGCCAGTGGA-3′ (SEQ ID NO: 9) for SARS-CoV-2 N.

The two peptides (#120 (SEQ ID NO: 1) and #125 (SEQ ID NO: 5)) showed astrong inhibition of SARS-CoV-2 infection in Calu-3 cells with IC₅₀ andIC₉₀ values of 0.03 and 0.51 μM for #120 (SEQ ID NO: 1), and 0.16 and1.3 μM for #125 (SEQ ID NO: 5) (FIG. 4).

Example 6 Plaque Inhibition Assay

A SARS-CoV-2 plaque inhibition assay was performed using African greenmonkey kidney Vero E6 cells purchased from the Korean Cell Line Bank(Seoul, Korea). The cells were incubated in 95% air and 5% CO₂ at 37° C.in Dulbecco's modified Eagle's medium (DMEM, Thermo Fisher Scientific,Waltham, Mass., USA) containing 10% fetal bovine serum (FBS, ThermoFisher Scientific), 25 mM HEPES, 100 U/mL penicillin, and 100 μg/mLstreptomycin. SARS-CoV-2 (NCCP No. 43326) was provided by the NationalCulture Collection for Pathogens (Osong, Korea).

Vero E6 cells (2×10⁵ cells/well) were cultured in 6-well plate at 37° C.in a CO₂ incubator overnight. The cells were washed withphosphate-buffered saline (PBS) and then added SARS-CoV-2 in PBS at MOI0.01. The plates were incubated for 1 h at 37° C. in a CO₂ incubator andthen 2 mL of DMEM containing 2% FBS was added to each well. The plateswere incubated at 37° C. in a CO₂ incubator for 3 days. The virusculture supernatants were harvested and centrifuged at 2,000 rpm for 10min at 4° C. to remove cell debris. The amplified viruses werequantified by plaque assay. Vero E6 cells (7×10⁵ cells/well) were platedin 6-well plates and then cultured until a monolayer was formed at 37°C. in CO₂ incubator. The cells were washed with PBS and infected with10-fold serial dilutions of the amplified SARS-CoV-2 culturesupernatants. After 1 h incubation, the supernatants were removed andthe wells were overlaied with 3 mL DMEM/F12 medium (Thermo FisherScientific) containing 2% Oxoid agar and N-p-Tosyl-L-phenylalaninechloromethyl ketone (TPCK, 1 μg/mL)-treated trypsin. Plaques wereallowed to develop for 3 days at 37° C. Plates were stained with crystalviolet (0.1% crystal violet in 20% methanol) for 1 h, prior toenumeration. SARS-CoV-2 amplification and cell culture procedures wereperformed according to biosafety level 3 (BSL-3) conditions.

To investigate inhibitory activities of peptides against SARS-CoV-2infection, we performed plaques inhibition assay in Vero E6 cells. At 10μM concentration, peptides were able to reduce SARS-CoV-2 plaquesformation by 15-74%. Among these peptides, #125 (SEQ ID NO: 5) wasobserved 75% reduction in SARS-CoV-2 plaques formation. #120 (SEQ IDNO: 1) and #121 (SEQ ID NO: 2) peptide showed approximately 15%inhibition of SARS-CoV-2 plaques (FIG. 5A). Treatment with #125 peptide(SEQ ID NO: 5) significantly inhibited the SRAS-CoV-2 plaque formationin a dose-dependent manner. The estimated IC₅₀ values for #125 peptide(SEQ ID NO: 5) was 0.46 μM (FIG. 5B).

Example 7 IC₅₀ Values of Assays

In this experiment, the inhibitory properties of three 39-mer HR2analogue peptides were studied by different antiviral assay methods. Thesummary of IC₅₀ values in these assays is provided in Table 5.

TABLE 5 Estimated IC₅₀ Values for Peptides #120 (SEQ ID NO: 1), #121(SEQ ID NO: 2), and #125 (SEQ ID NO: 5) in Antiviral Assays IC₅₀ Assay#120 #121 #125 SARS-CoV-2 Spike-mediated cell-cell fusion 0.75 0.72 4.4SARS-CoV-2 pseudovirus infection in 0.24 0.16 1.2 Calu-3 cellsSARS-CoV-2 pseudovirus infection in >10 >10 2.4 VeroE6 TMPRSS2-dependentplasma membrane <1 <1 1.7 pathway in VeroE6-TMPRSS2 SARS-CoV-2 RNAquantification 0.03 ND 0.16 SARS-CoV-2 plaques inhibition assay ND ND0.46

The peptide #120 (SEQ ID NO: 1) was able to strongly decrease the viralRNA load with IC₅₀=0.03 μM. The pseudovirus infection was decreased in adose dependent manner in Calu-3 cells and VeroE6-TMPRSS2, with IC₅₀values in the low nanomolar range. Despite these strong inhibitoryproperties in the mentioned assays, #120 (SEQ ID NO: 1) did not producesignificant inhibitory properties in SARS-CoV-2 pseudovirus infection inVeroE6 cells as well as in the SARS-CoV-2 plaques inhibition assay.Peptide #121 (SEQ ID NO: 2) produced a profile similar profile to #120(SEQ ID NO: 1). This indicates strong inhibitory properties of #120 (SEQID NO: 1) and 121 (SEQ ID NO: 2) in membrane-mediated virus fusionprocess and weak effect in blocking the endocytosis pathway.

Peptide #125 (SEQ ID NO: 5) produced favorable inhibition in the rangeof the used antiviral assays. The peptide was effective in cell-cellfusion and pseudovirus assays in the low micromolar range. Peptide #125(SEQ ID NO: 5) strongly inhibited the viral RNA with IC₅₀=0.16 μM. Moreimportantly, peptide #125 inhibited the SARS-CoV-2 plaque inhibitionassay in the nanomolar range with IC₅₀=0.46 μM. This indicates thatpeptide #125 (SEQ ID NO: 5) can block both the membrane-dependent orendocytosis-dependent virus entry to the cells.

Based on these assays, the peptides #120 (SEQ ID NO: 1), 121 (SEQ ID NO:2) and 125 (SEQ ID NO: 5) can be a base for anti-SARS-CoV-2 therapy. Ofspecial interest, peptide #125 (SEQ ID NO:5) inhibited the virus entryin all of the used assays and in different cell types.

It is to be understood that the anti-SARS-CoV-2 fusion peptides are notlimited to the specific embodiments described above, but encompass anyand all embodiments within the scope of the generic language of thefollowing claims enabled by the embodiments described herein, orotherwise shown in the drawings or described above in terms sufficientto enable one of ordinary skill in the art to make and use the claimedsubject matter.

We claim:
 1. An anti-SARS CoV-2 fusion peptide comprising a peptidehaving an amino acid sequence selected from the group consisting of SEQID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO:
 5. 2. The anti-SARSCoV-2 fusion peptide of claim 1, comprising a peptide having the aminoacid sequence of SEQ ID NO:
 2. 3. The anti-SARS CoV-2 fusion peptide ofclaim 1, comprising a peptide having the amino acid sequence of SEQ IDNO:
 3. 4. The anti-SARS CoV-2 fusion peptide of claim 1, comprising apeptide having the amino acid sequence of SEQ ID NO:
 4. 5. The anti-SARSCoV-2 fusion peptide of claim 1, comprising a peptide having the aminoacid sequence of SEQ ID NO:
 5. 6. A method for conducting a SARS CoV-2inhibition assay comprising: (a) providing a test inhibitor; (b)providing a reference inhibitor; (c) conducting the SARS CoV-2inhibition assay on the test inhibitor to obtain results for the testinhibitor; (d) conducting the SARS CoV-2 inhibition assay on thereference inhibitor to obtain results for the reference inhibitor; and(e) comparing the results for the test inhibitor to the results for thereference inhibitor to determine whether the test inhibitor inhibitsSARS CoV-2; wherein the reference inhibitor comprises the anti-SARSCoV-2 fusion peptide of claim
 1. 7. The method of claim 6, wherein theassay is a cell-cell fusion assay.
 8. The method of claim 6, wherein theassay is a SARS CoV-2 plaque formation assay.
 9. A pharmaceuticalcomposition comprising the anti-SARS CoV-2 fusion peptide of claim 1 anda pharmaceutically acceptable carrier.
 10. A pharmaceutical compositioncomprising an expression system encoding at least one peptide comprisingan amino acid sequence selected from the group consisting of SEQ ID NOs:2-5, and a combination thereof.
 11. The pharmaceutical composition ofclaim 10, wherein the expression system encodes a peptide comprising theamino acid sequence of SEQ ID NO:
 2. 12. The pharmaceutical compositionof claim 10, wherein the expression system encodes a peptide comprisingthe amino acid sequence of SEQ ID NO:
 3. 13. The pharmaceuticalcomposition of claim 10, wherein the expression system encodes a peptidecomprising the amino acid sequence of SEQ ID NO:
 4. 14. Thepharmaceutical composition of claim 10, wherein the expression systemencodes a peptide comprising the amino acid sequence of SEQ ID NO: 5.15. A method of inhibiting SARS CoV-2 infection of a cell comprisingadministering a composition comprising at least one peptide according toclaim 1 or a combination thereof to a subject in need thereof.
 16. Themethod of claim 15, wherein the peptide comprises a peptide the aminoacid sequence of SEQ ID NO:
 2. 17. The method of claim 15, wherein thepeptide comprises a peptide having the amino acid sequence of SEQ ID NO:5.